Derivatives of pyridazinone and methods for their production

 

(57) Abstract:

Describes the new derived pyridazinone represented by the formula (I), where X represents a hydrogen atom, a lower alkoxygroup or halogen atom; Y is a single bond or an oxygen atom; a represents alkylenes group with straight or branched chain, having from 1 to 10 carbon atoms; and R2each represents: represents a carbonyl group; R2represents the lower alkenylphenol group, pyridyloxy group which may be substituted by a lower alkyl group or amino group, pyrrolidino group, personilnya group, indolenine group, isooxazolyl group, which is substituted by a lower alkyl group; represents sulfonyloxy group, R2represents an alkyl group having from 1 to 10 carbon atoms, or lower alkenylphenol group; R1represents a hydrogen atom or a lower alkyl group; R3represents a hydrogen atom or a lower alkyl group; R4represents a hydrogen atom or a lower alkyl group; R5represents a hydrogen atom or a lower alkyl group, or their pharmaceutically acceptable salts. New is isany how to get the above compounds. 5 C. and 16 h.p. f-crystals, 22 PL.

This invention relates to new derivatives of pyridazine having activity in the treatment of nephritis and/or activity in protecting against endotoxin shock, and to methods for their preparation. The publication of the provisional patent Japan N 23853/- 1988 described that benzosulfimide derivatives such as 6-(2-benzosulfimide-5-yl)-4,5-beginreading - 3(2H)-he, exhibit antithrombotic activity. In addition, international patent publication PCT N WO 92/-15558 described, that the derivatives of benzensulfonamidelor, such as 6-(2-[(4-chlorophenyl)sulfoaluminate] -indan-5-yl)-4,5 - dihydropyridine-3(2H)-he have an antagonistic effect against thromboxane A2.

The publication of the provisional patent Japan N 124279/-1978 described, that the derivatives of pyridinylmethyl, such as 5-methyl-6-(4-[2-(pyridine-3-ylcarbonyl)ethyl] phenyl)-4,5 - dihydropyridine-3(2H)-he has an antiallergic activity. In addition, the publication of the provisional patent Japan N 212552/1986 described that benzensulfonamidelor derivatives such as 6-(4-[2-[phenylcarbonylamino] phenyl) pyridazin-3(2H)-it, show prototrophic now, heavily infected with gram-negative bacteria, traditionally used such agents as steroid hormones, Aprotinin (a protease inhibitor) and dobutamine (heart means).

In addition, as a means to ensure jade traditionally used prednisone (a steroid agent), cyclophosphamide (immunosuppressant), dipyridamole, dilazep (protivotrevozhny agent) and heparin (an anticoagulant).

The invention

The object of the present invention are new with excellent effect in the treatment of nephritis and/or superior action in preventing endotoxin shock and having a smaller adverse effect on the circulatory system derived pyridazine, as well as the way they are received.

Thus, the present invention relates to the derivatives of pyridazine represented by the formula

< / BR>
where X represents a hydrogen atom, a lower alkyl group which may have a Deputy (deputies), the lower alkoxygroup, carboxypropyl, alkoxycarbonyl group, a nitrogroup, cyano, lower allylthiourea, hydroxy group, amino group, which may have a Deputy (deputies), or halogen atom;

Y ablanovo group, which may have a double bond;

B and R2each is as follows:

B represents a carbonyl group or thiocarbonyl group; and R2represents an alkyl group having from 1 to 10 carbon atoms which may be substituted, cycloalkyl group having from 3 to 6 carbon atoms, lower alkenylphenol group, phenylseleno lower alkenylphenol group, a lower alkoxygroup, which may have a Deputy (deputies), fenoxaprop, lower alkylamino, lower alkynylamino, phenylaminopropyl, lower alkenylacyl, monocyclic or bicyclic aromatic heterocyclic group which has at least one nitrogen atom, oxygen atom and sulfur atom as heteroatoms (atoms) and may have a Deputy (deputies) or aryl group which may have a Deputy (deputies) or aryl group which may have a Deputy (deputies), or

B represents sulfonyloxy group; and R2represents an alkyl group having from 1 to 10 carbon atoms which may be substituted, cycloalkyl group having from 3 to 6 carbon atoms, lower alkenylphenol group, a hair dryer, the forge group, which has at least one nitrogen atom, oxygen atom and sulfur atom as heteroatoms (atoms) and may have a Deputy (deputies);

R1represents a hydrogen atom, a lower alkyl group which may be substituted, or lower alkenylphenol group;

R3represents a hydrogen atom or a lower alkyl group which may be substituted;

R4represents a hydrogen atom or a lower alkyl group; and

R5represents a hydrogen atom or a lower alkyl group,

or their pharmaceutically acceptable salts, and to the way they are received.

Description of the preferred implementations of the invention

The present invention is explained in detail in the following description.

In the formula (I), X represents a hydrogen atom, a lower alkyl group which may be substituted, preferably having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms; a lower alkoxy group, preferably containing from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms; campochiaro from 2 to 5 carbon atoms, particularly preferably from 2 to 4 carbon atoms; a nitro-group; a cyano; a lower allylthiourea, preferably containing from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms; hydroxy group; an amino group which may be substituted; or a halogen atom such as chlorine, bromine, iodine and fluorine. As Vice-alkyl group which may be substituted, you can specify a halogen atom; a lower alkoxygroup; an amino group which may be substituted by a group mono - or di - lower alkyl or acyl group; or a lower allylthiourea. As substituents of the amino group, you can specify a lower alkyl group, acyl group, lower alkoxycarbonyl group, karbamoilnuyu group, thiocarbamoyl group (the nitrogen atom of the specified carbamoyl group or thiocarbamoyl group may be optionally substituted by 1 or 2 lower alkyl groups and lower alkylcarboxylic group and, in addition, the substituted amino group includes an amino group in which the ends of the two substituents at the nitrogen atom connected with the formation of a cyclic structure, such as a group pyrrolidino, piperidino, peligrosas-1-yl, morpholino, tiomo the converted lower alkyl group, lower alkenylphenol group, acyl group, aryl group or the like).

In the formula (I), Y represents a single bond; oxygen atom or a sulfur atom; preferably a single bond.

In the formula (I) And represents a straight or branched alkylenes group which may have a double bond, preferably a group having from 1 to 10 carbon atoms, more preferably from 2 to 10 carbon atoms, particularly preferably from 2 to 6 carbon atoms. As such specific examples include methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethine group, octamethylene group, nonmelanoma group, 2-methyltetrahydrofuran group, 2-atinternational group and 1-butenylamine group (hereinafter, a numeral indicating the position of a branched chain or a double bond, shall be counted from the carbon atom from the structure of Y, which are attached in the formula (I)), preferably methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, 2-methyltetrahydro g is ebonyjoy group or sulfonyloxy group. When a represents a carbonyl group or thiocarbonyl group, R2in the formula (I) represents an alkyl group having from 1 to 10 carbon atoms which may be substituted, preferably a group having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms; cycloalkyl group having from 3 to 6 carbon atoms, lower alkenylphenol group, preferably having from 2 to 7 carbon atoms; more preferably from 2 to 5 carbon atoms; phenylseleno lower alkenylphenol group, preferably having from 2 to 7 carbon atoms in alkenyl, more preferably from 2 to 5 carbon atoms in alkenyl; a lower alkoxy group which may have a Deputy, preferably having from 1 to 6 carbon atoms; more preferably from 1 to 4 carbon atoms; phenoxy group; a lower alkylamino group, preferably having from 1 to 6 carbon atoms; more preferably from 1 to 4 carbon atoms; lower alkynylamino group, preferably having from 2 to 7 carbon atoms; more preferably from 2 to 5 carbon atoms; phenylaminopropyl; lower alkenylamine group preferably having from 2 to 7 carbon atoms; more preferably from 2 to 5 carbon atoms is d one nitrogen atom, oxygen and sulfur as a heteroatom and may have a Deputy; or aryl group which may be substituted. When is sulfonyloxy group, R2represents an alkyl group having from 1 to 10 carbon atoms which may be substituted is preferably a group having from 1 to 6 carbon atoms; more preferably from 1 to 4 carbon atoms, cycloalkyl group having from 3 to 6 carbon atoms, lower alkenylphenol group, preferably having from 2 to 7 carbon atoms; more preferably from 2 to 5 carbon atoms; phenylseleno lower alkenylphenol group, preferably having from 2 to 7 carbon atoms in alkenyl, more preferably from 2 to 5 carbon atoms in alkenyl; or monocyclic or bicyclic aromatic heterocyclic group which has at least one heteroatom selected from a nitrogen atom, oxygen and sulfur, and may have a Deputy.

As substituents for alkyl groups in R2here may be mentioned a halogen atom, a lower alkoxygroup, an amino group which may be substituted by one or two alkyl group or lower acyl group; or a lower allylthiourea.

As a researcher the ve lowest alkoxygroup, which may have a Deputy, you can specify, for example, the lower alkoxygroup, which can be a substituted phenyl group. As a monocyclic or bicyclic aromatic heterocyclic group which has at least one nitrogen atom, oxygen atom and sulfur atom as the heteroatom(s) and may have a substituent(s) (e.g Peregrina group, furilla group, thienyl group, piratininga group, pyrimidinyl group, pyridazinyl group, pyrrolidine group, imidazolidinyl group, pyrazolidine group, kinolinna group, izochinolina group, indayla group, isoindolyl group, thiazolidine group, isoxazolyl group, oxazoline group, chinadaily group, thienopyrimidine group, trainline group, tetrataenia group, khinoksalinona group, benzothiazoline group, benzothiazolyl group, benzoxazolyl group, benzimidazolyl group, isothiazolinone group, phthalazinone group, or benzoperylene group, each of which may be substituted by 1 to 4 substituents selected from the group comprising lower alkyl group, halogeno-lower alkyl group, lower alkoxygroup, lower alkylthio is luminograph, allmenalp, halogen atom, fenoxaprop, carboxypropyl, lower alkoxycarbonyl group, a lower alkylcarboxylic group, lower alkylcarboxylic group, karbamoilnuyu group, mono-lower alkylcarboxylic group and a di-lower alkyl-karbamoilnuyu group. As the aryl group which may have a substituent(s), you can specify, for example, phenyl group which may be substituted by 1-3 substituents selected from the group comprising lower alkoxygroup, lower phenylseleno alkoxygroup, a halogen atom, a hydroxy-group, triptorelin group, a nitrogroup, amino group, lower alkyl group, di-lower alkylamino.

In the formula (I) R1represents a hydrogen atom, a lower alkyl group which may be substituted, preferably containing from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms; or lower alkenylphenol group, preferably having from 2 to 7 carbon atoms, more preferably from 2 to 5 carbon atoms. As substituents for alkyl groups, you can specify a phenyl group, pyridyloxy group, follow group, thienyl group and piratininga may be substituted, preferably having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms. As substituents for alkyl groups, you can specify a cyano, an amino group which may be substituted, alkylcarboxylic group, alkoxycarbonyl group, hydroxycarbonyl group, phenyl group which may be substituted, pyridyloxy group, follow group, thienyl group, personilnya group, tetrazolyl group or piperazinilnom group.

As the amino group which may be substituted, can be mentioned above for X.

As phenyl group which may be substituted, can be mentioned above for R2.

In the formula (I) each of the radicals R4and R5represents a hydrogen atom or a lower alkyl group, preferably having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms.

Of the target compounds (I) of the present invention as an example of preferred group of compounds is possible to specify, for example, the group comprising compounds having parnou communication,

(C1): And is alkalinous group with straight or branched chain, which may have a double bond, having from 2 to 10 carbon atoms;

(c2): And is alkalinous group with straight or branched chain, having from 3 to 6 carbon atoms;

(d1): B is a carbonyl group,

(d2): is sulfonylurea group,

(E1): R2is peredelnoj group which may have 1 or 2 substituent selected from the group consisting of lower alkyl group, halogen-(lower alkyl) group, a lower alkoxygroup, lower allylthiourea, the hydroxy-group, mercaptopropyl, cyano, amino group, substituted an amino group, a halogen atom, fenoxaprop, carboxypropyl, lower alkoxycarbonyl group, a lower alkylcarboxylic, lower alkylcarboxylic group, karbamoilnuyu group, mononessa alkylcarboxylic group and a di-lower alkylcarboxylic group, a lower alkyl group or lower alkenylphenol group

more preferably

(E2): R2is peredelnoj group which may have 1 or 2 substituent selected from the group comprising lower alkyl group, lower alkylamino and the amino group, lower alkyl group or lower BR> more preferably

(E4): R2is the vinyl group of the lower alkyl group,

(E5): R5is peredelnoj group which may optionally have 1 or 2 substituent selected from lower alkyl groups, lower alkylamino and amino group,

(f): R3is a hydrogen atom,

(g): R4is a hydrogen atom, and

(h): R5is a hydrogen atom.

As an example of a more preferred group of compounds, you can specify the group comprising compounds having the following characteristics:

(d1) and (E1) or (d2) and (E3).

As an example, even more preferred group of compounds, you can specify the group comprising compounds having the following characteristics:

(d1) and (E5) or (d2) and (E4).

As examples of particularly preferred group of compounds, you can specify the group comprising compounds having the following characteristics:

(b), (C1), (d1) (e1), (f), (g) and (h), or (b), (c1), (d2), (e3), (f), (g) and (h).

As an example, the most preferred group of compounds, you can specify the group comprising compounds having the following characteristics:

(d), (C2), (d1) (E5), (f), (g) and (h), or (b), (C2), (d2), (e4), (f), (g) and (h).

When the target compound (I) of the present invention has asymmetric atoms, both steric isomers based on asymmetric atoms, and their mixtures are included in the present invention.

In tables 1-5 are examples of target compounds of the present invention, however, the target join us the mu to the invention can be used for medical purposes or in free form, either in the form of pharmaceutically acceptable salts of this compound. As a pharmaceutically acceptable salt, you can specify salts of inorganic acids such as hydrochloride, sulfate, phosphate and hydrobromide, and organic acid salts such as acetate, succinate, fumarate, oxalate, maleate and methanesulfonate, especially the hydrochloride.

In addition, the salt of the target compound (I) may be in the form of a salt with the resin obtained, for example, with polyethylene resin having an amino group, a Quaternary amino group or a sulfonic acid group, or a resin having carboxypropyl, for example resin polyacrylic acid. This salt can also be a complex with a metal, such as iron and copper, or a salt of ammonium chloride. Thus, it should be considered that the target compound (I) and its salt include all intramolecular salts, adducts, complexes, solvate and hydrate of the compound.

The target compound (I) of the present invention may be administered or through the mouth or parenterally, and it can be used as a medical drug by mixing this compound with the additive, suitable for oral or parenteral administration. Medication can be a hard drug, the. In addition, when the target compound is introduced parenterally, it can be used in the form of injections.

The dose varies depending on age, weight and condition of the patient and the severity of the disease, but usually, the daily dose is preferably from 1 to 300 mg/kg, in particular from 3 to 100 mg/kg in the case of the introduction through the mouth, and preferably from 0.01 to 50 mg/kg, in particular from 0.1 to 20 mg/kg in the case of parenteral administration.

According to the present invention, the target compound can be obtained in the following ways:

The method of obtaining (A)

Among the target compounds (I), pyridazinone compound represented by formula

< / BR>
where W represents an oxygen atom or a sulfur atom, R21represents an alkyl group having from 1 to 10 carbon atoms which may be substituted, cycloalkyl group having from 3 to 6 carbon atoms, lower alkenylphenol group, phenylseleno lower alkenylphenol group, a lower alkoxygroup, which may have a substituent(s), fenoxaprop, lower alkylamino, lower alkynylamino, phenylaminopropyl, lower alkenylacyl, monocyclic or bicyclic heterocyclic aromatics the volume(s) and may have a substituent(s); or aryl group which may have a Deputy (deputies); and X, Y, A, R1, R3, R4, R5have the same values as above,

or its pharmaceutically acceptable salt can be obtained, for example, by reacting a derivative of pyridazinone represented by the formula

< / BR>
where X, Y, A, R1, R3, R4, R5have the same values as above,

or its salt with the compound represented by formula

< / BR>
where W and R21have the same values as above, its reactive derivative or salt, and, if necessary, transform the resulting compound into its pharmaceutically acceptable salt.

Method get ()

Of the target compounds (I) derived pyridazinone represented by the formula

< / BR>
where R22represents an alkyl group having from 1 to 10 carbon atoms which may be substituted, cycloalkyl group having from 3 to 6 carbon atoms, lower alkenylphenol group, phenylseleno lower alkenylphenol group, monocyclic or bicyclic aromatic heterocyclic group which has at least one nitrogen atom, oxygen atom or atom is P> have the same values as above,

or its pharmaceutically acceptable salt, can be obtained, for example, by reacting a derivative of pyridazinone represented by the formula

< / BR>
where X, Y, A, R1, R3, R4and R5have the same values as above,

or its salt with the compound represented by formula

R22-SO2Z, (IV)

where Z is a reactive residue and R22has the same meaning indicated above,

and, if desired, converting the compounds obtained into its pharmaceutically acceptable salt.

Method get ()

The target compound of formula (I) can also be obtained, for example, by oxidation of the compound represented by formula

< / BR>
where X, Y, A, R1, R2, R3, R4and R5have the same values as above,

and, if desired, converting the compounds obtained into its pharmaceutically acceptable salt.

In the above-described method of obtaining (A), when the compound (I-a) is obtained using substances (III) or its salt, the reaction can be carried out in the presence or absence of a condensing agent, if necessary, in the presence of acceptor condensing agents, such as 1,3-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and diethylphosphinic cyanide. As salts of the compound (III) can be used commonly used salt such as a salt of an alkali metal, alkaline earth metal salt and an organic amine. Preferably, when interacting with the compound (II) above pre-salt was converted into the free compound, and then typed in the response.

According to the above method of obtaining (A), when the compound (I-a) is obtained using the reactive derivative of compound (III), the interaction can be optionally conducted in the presence or absence of an acid acceptor in a suitable solvent. As the reactive derivative, you can use a conventional reactive derivative used in the condensation, for example galoyanized acid, mixed acid anhydride and active ester. As the salt of the reactive derivative can be used, for example, salt of an inorganic acid, such as a salt of hydrochloric acid, Hydrobromic acid and sulfuric acid.

Method for producing (B) RA acid in a suitable solvent.

The compound (I-b) can also be obtained by a one-time conversion of compound (II) in aminosilicone derivative in the reaction system through the use of an agent for the introduction of a silyl group, such as trimethylchlorosilane, triethylchlorosilane and tert-butyldimethylchlorosilane, and then use the compound (IV).

As the reactive residue of the compound (IV) can specify a group that nucleophile is removed, for example, a halogen atom, alkoxygroup lowest alkylsulfonates, benzolsulfonate, substituted lower alkyl, benzolsulfonate and triftormetilfullerenov.

In the above-described method of obtaining (a) and the method of obtaining (I) as a salt of compound (II) can be used, for example, salt of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid, or salt of an organic acid, such as succinic acid, fumaric acid and maleic acid.

As the acid acceptor, which can be used in the above-described method of obtaining (a) and the method of obtaining (In), you can specify a carbonate of an alkali metal such as potassium carbonate ioxid alkali metal, such as potassium hydroxide and sodium hydroxide, tri-(lower) alkylamine, such as triethylamine, tributylamine and diisopropylethylamine, tertiary amine such as 1,4-diazabicyclo[2,2,2] octane, 1,5-diazabicyclo [4,3,0]non-5-ene and 1,8-diazabicyclo[5,4,0]undec-7-ene, and aromatic amine such as pyridine, lutidine, kallidin and dimethylaniline.

The solvent used in the above-described method of obtaining (a) and the method of obtaining (I), can be any inert solvent which does not exert a harmful effect on both reaction methods of obtaining (a) and (b) and may include, for example, halogenated solvents such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as toluene and xylene; an ether solvent type, such as tetrahydrofuran, dioxane, diethyl ether and 1,2-dimethoxyethane; a ketone solvent type, such as acetone, and methyl ethyl ketone; an ester solvent type, such as ethyl acetate; acetonitrile; pyridine; 2,6-lutidine; dimethylformamide, dimethyl sulfoxide; 1,3-dimethyl-2-imidazolidinone; a mixture of these solvents and a combination of any of these solvents and water.

Methods of obtaining (a) and (b) may be conducted under cooling, and when heated, e.g. the>/P>The oxidation method for producing (S) can be carried out in the usual way and it is easy to implement, for example, by treating compound (V) 3-nitrobenzenesulfonate sodium in a suitable solvent in the native environment, exposing its redox transformation with the use of dimethyl sulfoxide in a mixture of hydrogen bromide-acetic acid in acid medium, or by halogenation with bromine, chlorine, etc. with immediate dehydrohalogenating halogenated derivative.

The solvent here you can comfortably use water, acetic acid, propionic acid, triperoxonane acid, methanesulfonate or a solution of hydrogen bromide in acetic acid.

In reactions of the present invention, when the starting compound (II) or (V) is used in connection with asymmetric atoms, can be obtained corresponding to the target compound (I), (I-a) or (I-b), respectively, without racemization of asymmetric atoms.

The original compound (II) according to the present invention can be obtained by reacting compounds represented by a formula

< / BR>
where R11is a hydrogen atom, a lower alkyl, Konya,

with hydrazine and, when R11is a hydrogen atom, if it is desired alkylate the amino group, for example, by the method, when the amino group and the corresponding aldehyde derivative is subjected to reductive alkylation in the presence of a suitable reducing reagent such as sodium borohydride and bartreatteher sodium [NaB(OCOCH3)3H], with subsequent oxidation.

In the above reaction, the interaction of the compounds (VI) and hydrazine can be conveniently implemented in a suitable solvent or in the absence of solvent.

The solvent may be any inert solvent which has no adverse effect on the reaction, and may include, for example, a lower alcohol, such as methanol and ethanol; lower aliphatic acid, such as acetic and propionic acid, an aromatic hydrocarbon, such as toluene and xylene, a simple ether, such as tetrahydrofuran and dioxane, water and a mixture of the above solvents and water. The reaction may conveniently be implemented in a wide temperature range, from room temperature up to the boiling temperature of the reaction mixture, for example, preferably from 10oC to 200oC, especially at a temperature of 20oC to 150

The original compound (VI) can be obtained, for example, by the way, if necessary, after protection of the amino group of the compound represented by formula

< / BR>
where X, Y, A and R11have the meanings specified above,

the specified connection is subjected to interaction with the compound represented by formula

< / BR>
where R6represents an ester residue;

and Z has the same meaning indicated above,

or with the compound represented by formula

< / BR>
where R41represents a lower alkyl group;

and R51is a lower alkyl group;

and then remove the ester residue and/or a protective group.

The original compound (VI) can also be obtained, for example, a method in which after protection of the amino group of the compound represented by formula

< / BR>
where X, Y, A and R11have the same values as above,

the specified connection is subjected to interaction with the compound represented by formula

< / BR>
where V represents a halogen atom; and Z and R41have the same values as above,

obtaining the compounds represented by formula (XI)

< / BR>
where R7is sob
the compound obtained is subjected to interaction with the compound represented by formula

< / BR>
where R6has the same meaning indicated above,

to obtain compounds represented by a formula

< / BR>
where X, Y, A, R6, R7, R11and R41have the same values as above,

and then the obtained compound is subjected to hydrolysis and/or remove the protective group.

In addition, the original compound (VI) can be obtained, for example, a method in which after protection of the amino group of the compound represented by formula

< / BR>
where X, Y, A and R11have the same values as above,

the specified connection is subjected to interaction with the compound represented by formula

< / BR>
where Z and R51have the same values as above,

to obtain compounds represented by a formula

< / BR>
where X, Y, A, R7, R11and R51have the same values as above,

the compound obtained is subjected to interaction with acetocarmine or similar connection with obtaining the compound represented by formula

< / BR>
where X, Y, A, R6, R7, R11and R51have the same values as above,

and an amino group, you can specify commonly used protective group for amino group, for example acyl group such as acetyl group and calolina group.

As the ester residue can be specified, for example, a lower alkyl group.

In this description as the lower alkyl groups can be specified, for example, alkyl group having from 1 to 6 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group, isopentyl group, neo-pencilina group and n-exilda group, preferably from 1 to 4 carbon atoms, especially preferably from 1 to 3 carbon atoms. As the lower CNS group, you can specify, for example, alkoxygroup having from 1 to 6 carbon atoms, such as metaxylene group, amoxilina group, n-propoxyphene group, isopropoxyphenyl group, butoxylate group, pentoksila group and isopentene group, in particular alkoxygroup having from 1 to 4 carbon atoms. As the lower alkenylphenol group, you can specify, for example, alkyl group having 2 to 7 carbon atoms, such as vinyl group, 1-protanilla group, allyl group, 1-methylaniline group, 1-, 2 - enelow group, having from 2 to 5 carbon atoms.

In the present description of the substituted amino group includes mono- (lower alkyl) amino group, di(lower alkyl) amino group, allmenalp, N-(lower alkyl)-N-(lower alkoxycarbonyl) amino group, N-(lower alkyl)-N-carbamoylation, N-(lower alkyl)-N-thiocarbamoylation (the nitrogen atom of the specified carbamoyl group or thiocarbamoyl group may be optionally substituted by 1 or 2 lower alkyl groups), and (lower alkyl)-karbamoilnuyu group and further includes the amino group, in which the ends of the two substituents at the nitrogen atom associated with the formation of a cyclic structure, such as pyrolidine group, piperidino group, peligrosas-1 silt group, Martinova group, thiomorpholine group and pieperazinove group (the nitrogen atom in the 4-th position of the specified piperazino group may be optionally substituted lower alkyl group, lower alkenylphenol group, acyl group, aryl group, or so on).

As the acyl group, you can specify, for example, formyl group; (lower alkyl) carbonyl group having 2 to 7 carbon atoms, such as acetyl group, proposalsa group, Butyrina group, ing group, having from 2 to 4 carbon atoms; and lower alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, phenoxycarbonyl group and hexyloxymethyl group, preferably lower alkoxycarbonyl group having from 2 to 4 carbon atoms.

Lower alkyl group, lower alkoxygroup and lower Alchemilla group can be branched or unbranched.

As the halogen atom, you can specify chlorine, bromine, fluorine and iodine.

Examples

The present invention is described in detail with reference to test examples and examples, but the present invention is not limited to these examples. In examples 1-29, examples 65 and 66, examples 77-86 and example 88 described starting compound, and examples 30-64, examples 67-76 (in Russian), example 87 and examples 89-103 described the target of the connection.

Test example 1. Protonephridia activity

Rabbits were immunized with adjuvant and faction renal, glomerular base membrane obtained from WKY rats, and then the rabbits were collected solid is nutrivene was administered to male rats WKY (age 8 weeks) in 2.5 ml of diluted nephrotoxic serum for 1 kg of body weight, to call jade. The usual group of animals was injected intravenously same amount of saline.

One experimental group consisted of 6 rats. Each compound to be tested, suspended in purified water using a small amount of Tween 80 (trademark, produced by Nacalai Tescu To.) oral and injected a dose of 30 kg/kg/10 ml 2 times a day for 8 days. The normal group and the control group of animals orally was administered the same amount of purified water. On the seventh day, rats were placed in the cell metabolism and within 24 h were collected urine. Measuring the concentration of protein in the urine by the method of sulfosalicylic acid, was determined by the amount of released protein (mg/day). The degree of suppression of the allocation of the protein was calculated by the following equation:

< / BR>
The results are shown in table 6. As can be easily seen from this table, the selection of protein in the group of rats that were administered the target compounds of the present invention, is specifically inhibited with a high degree of suppression component from 65 to 90%.

One experimental group consisted of 4 rats. Each compound to be tested, suspended in purified water using a small Malinin awake rats. We investigated the magnitude of systolic blood pressure and pulse rate using the tail cuff KN-210 (trade mark, produced by Natsume Seisakusho) in terms of pre-treatment for 15 minutes. Degree appropriate changes was calculated by the following equations:

< / BR>
The results are shown in table 7.

As is clear from table 7, it can be understood that the target compounds of the present invention have less impact on heart rate and blood pressure and have less side effects on the circulatory system.

Test example 3. Side effects on the circulatory system

Twelve males and females half-dogs (6 dogs at one test compound) was anestesiologi intravenous infusion of 30 mg/kg pentobarbital sodium. After that, the depth of anesthesia was maintained constant by injection of 5 mg/kg pentobarbital sodium, and artificial respiration was carried out through a tube inserted into the trachea. In the left and right berenyi veins were inserted hollow needle to inject the anesthetic solution and needle for the introduction of each of the test compounds. In the right bedranol artery were inserted hollow needle detenue artery were inserted hollow needle for measuring the pressure in the left ventricle of the heart, this end part of the needle was kept in the left ventricle. Compound was dissolved in 25% solution of a hydroxy--/ cyclodextrin and injected intravenously. The number of input solution was 0.15 ml/kg of the compound was administered at a dose of 300 mg/kg and measured values of blood pressure, pulse rate and pressure in the left ventricle (DLI) before the introduction and after 1 hour after administration of the compound. As an indicator of sacramemto heart took the maximum rate of increase of pressure in the left ventricle (dp/dtmax). Blood pressure was measured using arterial needles, using the amplifier pressure AP-621G (trademark, produced by Nihon Kodansha) and the pressure transducer. Average blood pressure was measured using a capacitive-resistive circuit AD-601G (trademark, produced by Nihon Codensa, the time constant of 3 seconds). As for the pressure in the left ventricle, DLG was measured in the same way that blood pressure using the pressure booster via a pressure transducer with micromechanical catheter SPG-350 (trade mark, produced by Millar instruments), and the value dp/dtmax(maximum speed increase DLI) was determined A pulse was measured by the frequency of heart AC-601G (trademark, produced by Nihon Kodansha), and pulse pressure wave of the left ventricle was used as a trigger.

According to the following equations were calculated corresponding values of the degree of changes in blood pressure, pulse rate and the maximum rate of increase of pressure in the left ventricle (dp/dtmax)

< / BR>
Were measured maximum extent appropriate changes between doses of the tested compounds and the values after 1 hour after administration of the compounds; the data shown in table 8.

As is clear from table 8, it can be understood that the target compounds of the present invention have less impact on heart rate, blood pressure and the rate of increase of pressure in the left ventricle dp/dtmax(i.e., systolic force of the left ventricle) and have fewer side effects on the circulatory system.

Example 1. Getting the source to 29 example

To a solution of 45.5 g of methylhydrazine in 500 ml of dichloroethane add to 45.9 g oxalicacid and 5 drops of dimethylformamide and the mixture is stirred at room temperature for 3 hours Under ice cooling are added declaratively solution (60 ml), 1 h ( The reaction mixture was poured into ice water and the organic layer separated. After washing the organic layer with water and drying, the solvent is removed. The resulting crude crystals subjected to recrystallization from ethyl acetate with the receipt of 42.3 g of 4-[4-(acetylamino)butyl]-1-(3-methoxycarbonylpropionyl)benzene. So pl. 94-95oC.

Examples 2-5

Treating the corresponding starting compound in the same manner as in example 1, there were obtained compounds are shown in table 9.

Example 6

In 480 ml of 10 M hydrochloric acid are suspended to 43.0 g of 4-[4-(acetylamino)butyl]-1-(3-methoxycarbonylpropionyl) benzene and the mixture refluxed overnight. 10 M hydrochloric acid is removed, the resulting crude crystals (36.5 g) add 350 ml of acetic acid and 20.7 g of hydrazine monohydrate and the mixture is refluxed for 3 hours the Mixture is concentrated to half the amount of acetic acid to the concentrate was added 400 ml of diethyl ether and the precipitated crystals are collected by filtration. The crystals are dissolved in 200 ml of water and the solution neutralized with an aqueous solution of ammonia. The precipitated crystals are collected by filtration, dried and then recrystallized from methanol with polyceratia corresponding starting compound in the same way, as in example 6 were obtained the compounds shown in table 10.

Example 11

When cooled to dichlorethane suspension (250 ml) containing 12,83 g of [2-methyl-4-phthalimidobutyl] benzene and 9,29 g of succinic anhydride with ice add 24,86 g of anhydrous aluminum chloride and the mixture is stirred at room temperature for 2 hours, the Reaction mixture was poured into ice water and the organic layer separated. After washing the organic layer with water and drying, the solvent is removed. The resulting crude crystals subjected to recrystallization from a mixture of ethyl acetate and hexane, obtaining 16,11 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylmethyl) benzene. So pl. 142-143oC.

Example 12-14

Treating the corresponding starting compound in the same manner as in example 11, were obtained the compounds shown in table 11.

Example 15

To ethanol (500 ml), a solution to 15.06 g of 4-(2-methyl-4 - phthalimidobutyl)-1-(3-hydroxycarbonylmethyl) benzene type being 9.61 g of hydrazine monohydrate and the mixture is refluxed for 2.5 hours After cooling, the precipitated crystals are collected by filtration and subjected to recrystallization from ethyl acetate to obtain 8,14 g of 6-[4-(4-amino-2-eastwoodiae starting compound in the same way, as in example 15, were obtained the compounds shown in table 12.

Example 19

In 200 ml of acetic acid are suspended 15,00 g of 6-[4-(4 - aminobutyl)phenyl] -4,5-dihydropyridine-3-one. To this suspension was added 100 ml of 25% solution of hydrogen bromide in acetic acid and then 5.35 g of dimethylsulfoxide and the mixture is stirred at room temperature for 4.5 hours To the reaction mixture is added 400 ml of diisopropyl ether and the precipitated crystals are collected by filtration and subjected to recrystallization from methanol to obtain 18,94 g of the hydrobromide of 6-[4-(4-amino-2 - methylbutyl)phenyl]-4,5-dihydropyridine-3-one. So pl. 271-273oC (decomposes).

Examples 20 - 29

Treating the corresponding starting compound in the same manner as in example 19, were obtained the compounds shown in table 13.

Example 30

Under ice cooling to diethylformamide suspension (30 ml) containing 1.65 g of the hydrobromide of 6-[4-(4-amino-2-methylbutyl)phenyl] -4,5-dihydropyridine-3-she 0,78 g of nicotinic acid and 1.55 g of triethylamine are added dropwise dimethylformamide solution (10 ml) containing 1.06 g diethylphosphonate cyanide, and the mixture is stirred for 1 h, the Reaction mixture was poured into ice water and dropped the C methanol with the receipt of 1.11 g of 6-[4-(4-pyridine-3-ylcarbonyl) butyl)phenyl]pyridazin-3-one. So pl. 190 - 191oC.

Examples 31-47

Treating the corresponding starting compound in the same manner as in example 30, were obtained the compounds shown in tables 14-16.

Example 48

An aqueous solution (25 ml) containing 4,30 g of anhydrous potassium carbonate, is added to the suspension in which a 2.01 g of the hydrobromide of 6-[4-(4-aminobutyl)phenyl] pyridazin-3-it is suspended in ethyl acetate (40 ml) and tetrahydrofuran (10 ml). Under ice cooling to a mixture of 2.23 g of the hydrochloride of the acid chloride of nicotinic acid and the mixture is stirred for 3 hours the Precipitated crystals are collected by filtration, washed with water, dried and recrystallized from methanol to obtain 1.30 grams of 6-[4-(4 - pyridine-3-ylcarbonyl)-butyl)phenyl] pyridazin-3-one. So pl. coincides with the so pl. compounds of example 30.

Examples 49-51

Treating the corresponding starting compound in the same manner as in example 48 were obtained substances listed in table 17.

Example 52

1) 1,3-dimethyl-2-imidazolidinone suspension (75 ml) containing 7.51 g of 6-[4-(3-aminopropyl)phenyl] -4,5 - dihydropyridine-3(2H)-she added 7.50 g of triethylamine and the mixture is stirred for 10 minutes at room temperature. Then to the mixture add the more at room temperature for 1 h The reaction mixture was poured into ice water and the precipitated crystals are collected by filtration and recrystallized from acetonitrile to obtain of 5.39 g of 6-[4-(3-vinylsulfonate-propyl)phenyl] -4, 5 - dihydropyridin-3(2H)-she. So pl. 133-135oC.

2) To 25% suspension, hydrogen bromide-acetic acid, containing 5.30 g of 6-[4-(3-vinylsulfonylacetamido)phenyl] 4,5-dihydropyridin-3(2H)-she added 1.7 g of dimethylsulfoxide and the mixture is stirred at room temperature for 4.5 hours After removal of hydrogen bromide and acetic acid to the residue was added 100 ml of aqueous 15% solution of methylmercaptide sodium and the mixture is stirred for 1.5 h at 60oC. After cooling the mixture to neutralize the hydrogen chloride and the crystals are collected by filtration, washed with water, dried and then recrystallized from acetonitrile to obtain 3,90 g 6-[4-(3-(2-methylthioethyl)sulfonylamino)-phenyl] pyridazin-3(2H)-she. So pl. 173-174oC.

3) To acetate suspension (100 ml) containing are 5.36 g 6-[4-(3-(2-methylthioethyl)sulfonylamino)phenyl] pyridazin - 3(2H)-she added dropwise an aqueous solution (25 ml) containing 3,20 g metaperiodate sodium, and the mixture is stirred at room temperature for 1.5 hours the Reaction mixture was vailati) sulfonylamino)phenyl]pyridazin-3(2H)-she. So pl. 176-177oC.

4) Etilenglikolevye solution (25 ml) containing 2,48 g 6-[4-(3-(2-methylsulfinylphenyl)sulfonylamino)phenyl] - pyridazin-3(2H)-she, stirred at 180oC for 1 h, the Reaction mixture was poured into ice water and the precipitated crystals are collected by filtration, washed with water, dried and subjected to recrystallization from methanol, getting to 1.60 g of 6-[4-(3-vinylsulfonylacetamido)phenyl]pyridazin-3(2H)-she. So pl. 166-168oC.

Example 53

of 3.54 g of triethylamine is added to 1,3-dimethyl-2-imidazolidinone suspension (35 ml) containing 3,10 g of the hydrobromide of 6-[4-(3-aminopropyl)phenylpyridazin-3(2H)-she. Then to the mixture is added 15 ml of tertrahydrofuran ring solution containing 1,95 g chloroethylsulphonic, and the resulting mixture was stirred at room temperature for 5 hours, the Reaction mixture was poured into ice water and extracted with chloroform. After washing a chloroform layer with water and drying to remove the solvent. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 10:1) to obtain 1.19 g of 6-[4-(3-vinylsulfonylacetamido)phenyl]pyridazin(2H)-she. So pl. coincides with the so-coal-seam connection example 52-4).

Example 54

276 mg of triethylamine down)-she and 37 mg of dimethylaniline, and the mixture is stirred at room temperature for 30 minutes Under cooling with ice added 86 mg of trimethylchlorosilane and the mixture is stirred at room temperature for 2 hours. Again under ice cooling are added dropwise the dichloromethane solution (1 ml) containing 65 mg of chloroethylsulphonic, and the resulting mixture was stirred at room temperature for 30 minutes To the mixture add 5 ml of 1 M hydrochloric acid and the organic layer separated. After washing the organic layer with water and drying to remove the solvent. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 30:1) to give 73 mg of 6-(4-(3-vinylsulfonylacetamido)phenyl] -pyridazin-3(2H)-she. So pl. 197-198oC.

Examples 55 to 63

Treating the corresponding starting compound in the same manner as in example 54 were obtained compounds are shown in table 18.

Example 64

(1) Treating 6-[4-(4-AMINOPHENYL)phenyl] -4,5 - dihydropyridine-3(2H)-he and nicotinic acid in a similar manner as in example 30, was obtained 6-[4-(5-(pyridine-3-ylcarbonyl) pentyl)phenyl]-4,5-dihydropyridine-3(2H)-he is so pl. 133 - 134oC.

(2) Treating 6-[4-(5-(pyridine-3-ylcarbonyl is ylamino) pentyl)phenyl]pyridazin-3(2H)-he. So pl. same as that for the compound of example 37.

Example 65

Add 1.0 g of 10% palladium on coal (Pd/C) and 9.0 g of ammonium formate to methanol solution of 6-[2-chloro-5-(4-aminobutyl) phenyl]dihydropyridin-3(2H)-she. The resulting suspension is refluxed for 12 hours the Suspension is allowed to cool and then filtered and the filtrate is removed. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol/28% aqueous ammonia = 50:10:1) to give 1.3 g of 6-[5-(4-aminobutyl)phenyl]dihydropyridin-3(2H)-she. So pl. 128 - 130oC.

Example 66

Processing 6-[3-chloro-6-(4-aminobutyl)phenyl] -4,5 - dihydropyridine-3(2H)-he in a similar manner as in example 65 was obtained 6-[6-(4-amino)butyl)phenyl]-4,5-dihydropyridin-3-(2H)-he is so pl. 78 - 80oC.

Example 67

(1) When the inside temperature of the mixture equal to 0oC, N,N-dimethylacetamide suspension (270 ml) containing 9.0 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dihydropyridine-3(2H)-it added 50 g of anhydrous potassium carbonate and then 8.5 g of the hydrochloride of the acid chloride of nicotinic acid. The reaction mixture was stirred at the same temperature for 30 min and then poured into 200 ml of ice water. After stirring the mixture at room temperature is shat and then subjected to recrystallization from methanol, receiving 10.3 g of 6-[4-(4-pyridine-3 - ylcarbonyl) butyl) phenyl] -4,5-dihydropyridine-3(2H)-she. So pl. 178-179oC.

2) In acetic acid (100 ml) dissolve 10.0 g of 6-[4-(4 - pyridine-3-ylcarbonyl)butyl)phenyl] -4,5-dihydropyridine-3(2H)-she. To the solution add 100 ml of 25% solution of hydrogen bromide in acetic acid and the mixture is stirred at room temperature for 5 minutes To the mixture at room temperature is added 2.9 g of dimethylsulfoxide and the mixture was stirred at room temperature for 1 h the reaction mixture was added 150 ml of ethanol and the mixture is stirred for 2 hours In the mix even add 150 ml of diisopropyl ether and the resulting mixture is stirred for 2 hours Precipitated precipitated crystals are collected by filtration, washed with diisopropyl ether and then dissolved in aqueous ethanol. The solution is neutralized aqueous ammonia. Precipitated precipitated crystals are collected by filtration, washed with water and then subjected to recrystallization from methanol, getting 8.90 g of 6-[4-(4-(pyridine-3-ylcarbonyl)butyl)phenyl] pyridazin-3-(2H)-she. So pl. coincides with the so pl. compounds of example 30.

Example 68

(1) Processing corresponding to the original connection in the same manner as in example 67-(1), tx2">

(2) Treating 6-(4-(3-(pyridine-3-ylcarbonyl)propoxy) phenyl]-4,5-dihydropyridine-3(2H)-he same manner as in example 67-(2) was obtained 6-[4-(3-(pyridin-3-yl-carbylamine) propoxy)phenyl] pyridazin-3(2H)-he. So pl. coincides with the so pl. compounds of example 36.

Example 69

In hot ethanol (180 ml) dissolved 8,9 g of 6-[4-(4-(pyridine - 3-ylcarbonyl)butyl)phenyl] pyridazin-3(2H)-she. To the solution add 10 ml of 18% aqueous solution of hydrogen chloride in ethanol and the mixture is left to stand at room temperature. Precipitated precipitated crystals are collected by filtration and washed with cold ethanol, gaining 9.3 g of 6-(4-(4-(pyridine-3-ylcarbonyl)butyl)phenyl] pyridazin-3(2H)-he hydrochloride.

So pl. 245 - 247oC (recrystallization from ethanol).

Monohydrate hydrochloride, pl. 240 - 243oC (recrystallization from aqueous ethanol).

Examples 70-73

Treating the corresponding starting compound in the same manner as in example 69 were obtained compounds are shown in table 19.

Example 74

To 50 ml dimethylformamide solution containing 2.0 g of the hydrobromide of 6-[4-(4-(aminobutoxy)phenyl] -4,5-dihydropyridine - 3(2H)-it add 868 mg of nicotinic acid, 954 mg N-hydroxine is Yes and the reaction mixture was stirred at room temperature for 6 h and then poured into ice water. Precipitated precipitated crystals are collected by filtration and subjected to recrystallization from ethanol, receiving of 1.75 g of 6-[4-(4-pyridine-3-ylcarbonyl)butoxy) phenyl]pyridazin-3(2H)-she. So pl. 155 - 157oC.

Example 75

Processing corresponding to the original connection in the same manner as in example 74 was obtained 6-[4-(6-(pyridine-3 - ylcarbonyl)hexyl)phenyl] pyridazin-3(2H)-he. So pl. 178 - 179oC.

Example 76

Processing corresponding to the original connection 2-aminonicotinic acid in the same manner as in example 74 was obtained 6-[4-(3-(2-aminopyridine-3-ylcarbonyl)propoxy) phenyl] pyridazin-3(2H)-he is so pl. 232 - 234oC.

Example 77

1) Processing corresponding to the original connection in the same manner as in example 11, there was obtained 4-(4-phthalimidobutyl) - 1-(3-hydroxycarbonylmethyl)benzene. So pl. 133-134oC.

(2) Treating 4-(4-phthalimidobutyl)-1-(3 - hydroxycarbonylmethyl) benzene in the same manner as in example 15 was obtained 6-[4-(4-aminobutoxy)phenyl]-4,5 - dihydropyridin-3-(2H)-he. So pl. 191 - 192oC.

(3) Treating 6-[1-(4-aminobutoxy)phenyl] -4,5-dihydropyridin - 3-(2H)-he same manner as in example 19, there was obtained the hydrobromide 6-[4-(4-amino is output to the connection in the same way, as in example 1, there was obtained 4-(6-acetylaminophenol)-1- (3-methoxycarbonylpropionyl)benzene. So pl. 87 - 89oC.

2) Processing 4-(6-acetylaminophenol)-1-(3 - methoxycarbonylpropionyl) benzene in the same manner as in example 6, there was obtained 6-[4-(6-aminohexyl)phenyl]-4,5-dihydropyridin-3-(2H)- he. So pl. 153 - 154oC.

3) Treating 6-[4-(4-aminohexyl)phenyl] -4,5-dihydro - pyridazin-3-(2H)-he same manner as in example 19, there was obtained the hydrobromide 6-[4-(6-aminohexyl)phenyl]pyridazin-3(2H)-she. So pl. 251 - 253oC.

Example 79

1) Under cooling with ice add to 20.9 g of anhydrous aluminum chloride to 200 ml dichlorethane solution containing 10.0 g of [4-(acetylamino)butyl] benzene and 9,96 g of 2-chloropropionitrile, and the mixture was stirred at 5oC for 1 h, the Reaction mixture was poured into ice water and the organic layer is separated by the separation. After washing the organic layer with water and drying, the solvent is removed, getting 13,71 g of 4-[4-(acetylamino)butyl]-1-(2-chloropropionyl)benzene. So pl. 66-67oC.

(2) added dropwise 27.9 g of di(tert-butyl) ester of malonic acid to 300 ml of suspension containing of 5.17 g of 60% sodium hydride in dimethylformamide, and the mixture is stirred at room temperature t is but)butyl]-1-(2-chloropropionyl) benzene in dimethylformamide. The resulting mixture was stirred at room temperature for 1 h and additionally stirred at 50oC for 1 h, the Reaction mixture was poured into ice water and extracted with chloroform. After washing the organic layer with water and drying, the solvent is removed, getting 35,21 g of 4-[4-(acetylamino)butyl-1- ([3,3-di(tertbutoxycarbonyl)-2-methyl] propionyl)benzene in the form of an oily material.

(3) Add 70 ml triperoxonane acid to 600 ml of dichloromethane solution containing 35,21 g of 4-[4-(acetylamino) butyl]-1-([3,3-di(tert-butoxycarbonyl)-2-methyl] propionyl)- benzene. The mixture is stirred at room temperature for 1.5 h and then refluxed for 3 hours After removal of the solvent to the residue add 400 ml of acetic acid and the mixture is refluxed 3 hours Acetic acid is removed, receiving, and 19.6 g of 4-[4-(acetylamino)butyl]-1-[(3 - hydroxycarbonyl)-2-methyl]-propionyl)benzene.

IR-spectrum (in pure form), cm-1: 1720, 1680, 1610.

Mass spectrum (ESI) m/z: 323 (M + NH4).

(4) In 24 ml of 10 M hydrochloric acid are suspended 760 mg of 4-[4- (acetylamino)butyl] -1-[(3-hydroxycarbonyl)-2-methyl] - propionyl)benzene and the suspension is refluxed in accordance with Aut 880 mg of hydrazine monohydrate and the mixture is refluxed for 18 hours Remove the acetic acid and the residue is dissolved in water. The solution is alkalinized with ammonia and extracted with chloroform. After washing the organic layer with water and drying, the solvent is removed. The resulting crude crystals subjected to recrystallization from ethyl acetate, getting 421 mg of 6-[4-(4 - aminobutyl)phenyl]-4,5-dihydro-5-methylpyridazin-3(2H)-is it so pl. 135 - 137oC.

Example 80

(1) Treating 3-(phthalimidopropyl) benzene 2-chloropropionaldehyde in the same manner as in example 79-(1) was obtained 4-(3-phthalimidopropyl)-1-(2-chloropropionyl) benzene. So pl. 137 - 138oC.

(2) Treating 4-(3-phthalimidopropyl)-1-(2-chloropropionyl) benzene, di(tert-butyl) ester of malonic acid in the same manner as in example 79-(2) was obtained 4-[3-(phthalimidopropyl) -1-([3,3-di(tert-butoxycarbonyl)-2-methyl]propionyl)benzene. So pl. 103 - 105oC.

(3) Treating 4-[3-(phthalimidopropyl)-1-([3,3-di- (tert-butoxycarbonyl)-2-methyl] propionyl)benzene in the same manner as in example 79-3, was obtained 4-[3-(phthalimidopropyl) -1-([3-hydroxycarbonyl-2-methyl] propionyl)benzene. So pl. 122 - 123oC.

4) are Added to a suspension of 10.0 g of 4-[3-phthalimidopropyl]-1- [1-[(3-hydroxycarbonyl-2-methyl)propionyl] benzene in 200 ml atom dissolved in chloroform. After washing the organic layer with water and drying, the solvent is removed, the receiving of 6.61 g of 6-[4-(3-aminopropoxy)phenyl] -4,5-dihydro-5-methylpyridazin-3(2H)-she. So pl. 136 - 138oC.

Example 81

(1) Under cooling with ice add 1.64 g of anhydrous aluminium chloride to 18 ml dichlorethane solution containing 590 mg of [4-(acetylamino)butyl] benzene and 790 mg anhydride 2,3-dimethylethanol acid, and the mixture is stirred for 1 hour. The reaction mixture was poured into ice water and extracted with chloroform. After washing the organic layer with water and drying, the solvent is removed. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol (4:1)) to give 960 mg of 4-[4-(acetylamino)butyl] -1-[(3-hydroxycarbonyl-2,3 - dimethyl)propionyl]benzene.

IR-spectrum (in pure form), cm-1: 1710, 1680, 1610

Mass spectrum (ESI) m/z: 337 (M + NH4)

(2) was 4.02 g of 4-[4-(acetylamino)butyl]-1-[(3 - hydroxycarbonyl)-2,3-dimethyl)propionyl]benzene, add 80 ml of hydrazine monohydrate and the mixture is refluxed for 4 hours, the Reaction mixture was poured into ice water and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent is removed. The residue is purified chromate is Novotel)phenyl]-4,5-dihydro-4,5-dimethylpyridin-3(2H)-it.

IR-spectrum (in pure form), cm-1: 1680,

Mass spectrum (ESI) m/z : 278 (MH)+< / BR>
(3) To a solution of 2.20 g of 6-[4-(4-aminobutyl) phenyl]-4,5 - dihydro-4,5 - dimethylpyridin-3(2H)-she's in 44 ml of acetic acid add 44 ml of 25% solution of hydrogen bromide in acetic acid and the mixture is stirred at room temperature for 5 minutes. Then to the mixture is added 0.75 ml of DMSO, and the resulting mixture is stirred for 6 hours the Solvent is removed and the residue is dissolved in 150 ml of water. The solution is alkalinized with ammonia and extracted with chloroform. After washing chloroformate layer with water and drying, the solvent is removed. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol/28% aqueous ammonia (10:1:0,1)) to give 1.52 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dimethylpyridin-3(2H)-she. So pl. 162 - 163oC.

Example 82

(1) Processing [4-(acetylamino)butyl]benzene) and crotonville in the same manner as in example 79-(1) was obtained 4-[4-(acetylamino)butyl)-1-(2-butenyl)benzene. So pl. 64 - 66oC.

(2) To 15 ml of a methanol solution containing 510 mg of 4-[4- (acetylamino) butyl] -1-(2-butenyl) benzene and 1.69 g of acetocarmine add 1.1 ml of a 10% aqueous solution of sodium carbonate and the mixture is boiled on a column of silica gel (eluent: chloroform/methanol (40:1)), receiving 450 mg of 4-[4-(acetylamino)butyl]-1-(3-cyanobutane) benzene. So pl. 89 - 90oC.

(3) In 180 ml of 10-molar hydrochloric acid are suspended 7.50 g of 4-[4-(acetylamino)butyl] -1-(3-cyanobutane) benzene and the suspension is refluxed overnight under heating. The reaction mixture was concentrated to half volume and precipitated precipitated crystals are collected by filtration. After dissolution of the crystals in 110 ml of acetic acid to the solution add 5.29 g of hydrazine monohydrate and the mixture is refluxed under heating for 4 hours to Remove acetic acid and the residue is dissolved in water. The solution is alkalinized with ammonia and incubated over night. Precipitated precipitated crystals are collected by filtration, washed with water and dried and then subjected to recrystallization from a mixture of ethyl acetate and methanol, getting to 4.23 mg of 6-[4-(4-aminobutyl) phenyl]-4,5-dihydro-4-methylpyridazin-3(2H)-she. So pl. 118 - 120oC.

Example 83

(1) Processing [3-(4-phthalimidobutyl)-4-methyl]chlorobenzene succinic anhydride in the same manner as in example 11, was obtained [5-(4-phthalimidobutyl)-2-(3-hydroxycarbonylmethyl)-4 - methyl]chlorobenzene. So pl. 116 - 118oC.

(2) Processing [5-(4-phthalimidobutyl)-2-(3 - hydroxy[2-chloro-5-methyl-4-(4 - aminobutyl)phenyl]-4,5-dihydropyridine-3(2H)-he. So pl. 181 - 182oC.

(3) Treating 6-(2-chloro-5-methyl-4-(4-aminobutyl)phenyl]-4,5 - dihydropyridine-3(2H)-he same manner as in example 65 was obtained 6-[3-methyl-4-(4-aminobutyl)phenyl] -4,5 - dihydropyridine-3(2H)-he. So pl. 145 - 147oC.

Examples 84-86

Treating the corresponding starting compound in the same manner as in example 67 (1), were obtained substances listed in table 20.

Example 87

Add 690 mg of nicotinic acid and 760 mg of N-hydroxybenzotriazole to 80 ml dimethylformamide solution containing 1.39 g of 6-[4-(4-(aminobutoxy)phenyl]-4,5 - dimethylpyridin-3(2H)-she. Under ice cooling to a mixture of 1.08 g of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and the reaction mixture was stirred at room temperature for 3 h and then poured into ice water. The precipitated crystals are collected by filtration and subjected to recrystallization from 2-propanol, receiving of 1.41 g of 6-[4-(4-pyridine-3-ylcarbonyl)-butyl)phenyl] -4,5-dimethylpyridin - 3(2H)-she. So pl. 211 -212oC.

Example 88

Processing 6-[3-methyl-4-(4-aminobutyl)phenyl] -4,5 - dihydropyridine-3(2H)-he same manner as in example 87 was obtained 6-[3-methyl-4-(4-(pyridine-3-ylcarbonyl)butyl) phenyl] -4,5-dihydropyridine-3 (the zine-4-carboxylic acid thus as in example 87 was obtained 6-[4-(4-(pyridazin-4-ylcarbonyl)butyl)phenyl] pyridazin-3(2H)-he is so pl. 183 - 185oC.

Examples 90-95

Treating the corresponding starting compound in the same manner as in example 67(2), were obtained the compounds shown in table 21.

Examples 96-102

Treating the corresponding starting compound in the same manner as in example 69 were obtained compounds are shown in table 22.

Example 103

Processing 6-[4-(4-aminobutyl)phenyl] pyridazin-3(2H)-3-methyl-5-carboxymethoxy in the same manner as in example 87 was obtained 6-[4-(4-(3-methylisoxazol-5-ylcarbonyl)butyl) phenyl]pyridazin-3(2H)-he is so pl. 236 - 238oC.

Pyridazinone derivative (I) and its pharmaceutically acceptable salt, which are the target compounds of the present invention have excellent activity against jade and/or excellent protective effect against endotoxin shock. Therefore, the target compounds of the present invention are used as agents for the prevention and treatment of nephritis (e.g., glomerular nephritis, immunoglobulin a nephropathy, nephrotic syndrome, lupus nephritis, etc.,) and/or AG is used as agent for the prevention and treatment of endotoxin shock, which occurs in patients heavily infected with gram-negative bacteria.

The target compound (I) of the present invention are of low toxicity. For example, when introduced through the mouth mice hydrochloride of 6-[4-(4-(pyridine-3-ylcarbonyl)butyl)phenyl] pyridazin-3(2H)-she dose of 1000 mg/kg or when introducing the compound to mice intraperitoneally at a dose of 300 mg/kg when monitoring mice for 3 days in both cases was not observed any fatalities.

In addition, the target compounds of the present invention have excellent pharmacological activity, as described above, they also have a very small adverse effect on the circulatory system, so that they can be a medication with high security.

1. Derived pyridazinone represented by the formula I

< / BR>
where X represents a hydrogen atom, a lower alkoxygroup or halogen atom;

Y is a single bond or an oxygen atom;

A represents alkylenes group with straight or branched chain, having from 1 to 10 carbon atoms;

B and R2each is a: B represents a carbonyl group; R2pred or amino group, pyrrolidino group, personilnya group, indolenine group, isooxazolyl group, which is substituted by a lower alkyl group;

B represents sulfonyloxy group; R2represents an alkyl group having from 1 to 10 carbon atoms or lower alkenylphenol group;

R1represents a hydrogen atom or a lower alkyl group;

R3represents a hydrogen atom or a lower alkyl group;

R4represents a hydrogen atom or a lower alkyl group;

R5represents a hydrogen atom or a lower alkyl group,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where R1is a hydrogen atom.

3. Connection on p. 1, where R1is a lower alkyl group.

4. Connection on p. 1, where R3is a hydrogen atom.

5. Connection on p. 1, where B is a carbonyl group.

6. Connection on p. 1, where B is sulfonyloxy group.

7. Connection on p. 1, where Y is a single bond.

8. Connection on p. 1, where X is a hydrogen atom.

9. Connection on p. 1, where R2represents pyridyloxy LASS="ptx2">

10. Connection on p. 1, where R2represents a lower alkyl group or lower alkenylphenol group and B is sulfonyloxy group.

11. Connection on p. 1, where a is alkalinous group with straight or branched chain, having from 2 to 6 carbon atoms.

12. Connection on p. 1, where R2represents pyridyloxy group which may be substituted by a lower alkyl group, or amino group, R3is a hydrogen atom, B is a carbonyl group and Y denotes a single bond.

13. Connection on p. 1, where R2represents a lower alkyl group or lower alkenylphenol group, B denotes sulfonyloxy group and Y denotes a single bond.

14. Connection on p. 12, where R1is a hydrogen atom.

15. Connection on p. 13, where R1is a hydrogen atom.

16. Connection on p. 1 or 14, where R1is a hydrogen atom, R2represents pyridyloxy group which may be substituted by a methyl group or amino group, R3is a hydrogen atom, B is a carbonyl group and Y denotes a single bond.

17. Connection on p. 1 or 15, where R1

18. 6-[4-(4-(Pyridine-3-ylcarbonyl)butyl)phenyl] pyridazin-3(2H)-one or its pharmaceutically acceptable salt.

19. The method of obtaining pyridazinone compounds represented by formula (I-a)

< / BR>
where W represents an oxygen atom;

R21represents the lowest alkenylphenol group, pyridyloxy group which may be substituted by a lower alkyl group or amino group, pyrrolidino group, personilnya group, indolenine group, isooxazolyl group which may be substituted by a lower alkyl group;

X, Y, A, R1, R3, R4and R5specified in paragraph 1,

or its pharmaceutically acceptable salt, which includes the interaction derived pyridazinone represented by formula II

< / BR>
where X, Y, A, R1, R3, R4and R5specified in paragraph 1,

or its salt with the compound represented by formula III

< / BR>
where W and R21above,

its reactive derivative or salt, and if desired, converting the compounds obtained into its pharmaceutically acceptable salt.

20. The method of deriving pyridazinone represented by formula I-b

< / BR>
where R22is cf>3
, R4and R5specified in paragraph 1,

or its pharmaceutically acceptable salt, which includes the interaction derived pyridazinone represented by formula II

< / BR>
where X, Y, A, R1, R3, R4and R5specified in paragraph 1,

or its salt with the compound represented by formula IV

R23- SO2Z,

where Z is a reactive residue;

R23represents C1-10alkyl group which may be substituted by a halogen atom,

and, if desired, converting the compounds obtained into its pharmaceutically acceptable salt.

21. The method of deriving pyridazinone represented by the formula I

< / BR>
where X, Y, A, B, R1, R2, R3, R4and R5specified in paragraph 1,

or its pharmaceutically acceptable salts, which involves the oxidation of the compounds represented by formula V

< / BR>
where X, Y, A, B, R1, R2, R3, R4and R5specified in paragraph 1,

and, if desired, converting the compounds obtained into its pharmaceutically acceptable salt.

Priority points:

27.06.95 - PP.1 - 21;

06.02.96 - PP.1 - 21 variants radicals).

 

Same patents:

The invention relates to a derivative of oxazolidinone formula (I)

The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained by these methods

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new triazolylmethyl tertiary amine of the formula I, where A is a simple bond or lower Allenova group; B is a lower alkyl, a group (a), naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted with halogen or alkyl; D - ring group, (b) or benzofurazanyl; E - ring - 4H-1,2,4-triazole or 1H-1,2,4-triazolyl; R1- H, halogen, cyano-, nitro-group, CF3, lower alkyl or alkoxy; R2is hydrogen or halogen; R3- halogen, cyano-, nitro-, CF3or amino group, provided that when both R1and R2are chlorine atoms, And a methylene

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases
Up!