Triazolopyridine, the method of production thereof, pharmaceutical compositions and method of treatment

 

(57) Abstract:

Describes the new triazolopyridine compound of formula (I) in which R1is hydrogen or a lower alkyl group, R2is C2-C6-alkyl or C2-C6-cycloalkyl group; X is an oxygen atom, Y is (i) a group of the formula

< / BR>
in which R3and R4are hydrogen or lower alkyl group; R5and R6each independently means a hydrogen atom or a lower alkyl group; t and p independently represent an integer from 0 to 4, or its physiologically acceptable salt of joining the compounds of formula (I) have excellent anti-asthmatic, anti-allergic effect and excellent inhibitory activity against platelet activating factor and casinopalace of chemotaxis. 4 c. and 8 C.p. f-crystals, 2 PL.

The invention relates to new derivatives triazolopyridine exhibiting excellent anti-allergic, anti-inflammatory effect and an inhibitory effect on platelet activating factor (PAF), eosinophil chemotaxis and others, their preparation and application.

The PREVIOUS Level as medicines for many diseases. For example, in U.S. patent N 3915968 presents the compound of the formula:

< / BR>
in which R and R3independently are a hydrogen atom or lower alkyl, at least one of R and R3is lower alkyl; R and R2form together with the adjacent nitrogen atom a nitrogen-containing heterocyclic group, such as propalin, piperidine, piperazine and morpholine, or its salt. In U.S. patent N 4136182 presents the compound of the formula:

< / BR>
in which R is a hydrogen atom, phenyl or lower alkylcarboxylic; R1is morpholino or piperidino; R2is a hydrogen atom or lower alkyl, at least one of R or R2is a group that does not contain a hydrogen atom; when R is phenyl, then R1is morpholino and R2is lower alkyl, or its salt. In EP 248413 presents the compound of the formula:

< / BR>
or its salt, which are useful as bronchodilators to alleviate bronchospasm.

In EP 562439 presents the compound of the formula:

< / BR>
in which R1is a hydrogen atom, optionally substituted lower alkyl group or a halogen atom; R2and R3independently represent an atom C - 5-7-membered ring; X is an oxygen atom or S(O)p1where p is an integer from 0 to 2; Y is a group of the formula:

< / BR>
in which R4and R5independently are a hydrogen atom or optionally substituted lower alkyl group or a bivalent group derived from a 3-7-membered gomolla or heterocycle, which optionally is substituted;

R6and R7independently are a hydrogen atom, optionally substituted lower alkyl group, optionally substituted cycloalkyl group or optionally substituted aryl group, or may form together with the adjacent nitrogen atom a nitrogen-containing heterocyclic group that optionally is substituted;

m is an integer from 0 to 4 and n is an integer from 0 to 4, or its salt;

and as an example of a synthetic product the compound of the formula:

< / BR>
described as compounds exhibiting anti-asthmatic, anti-inflammatory and anti-allergic effect and inhibitory effect on platelet activating factor.

DISCLOSURE OF THE INVENTION.

There is a great need to create a new connection, which is blueprint asthma, anti-allergic medicines, etc.

By conducting various extensive studies, the present inventors received the first new connection [1,2,4]triazolo-[1,5-b]pyridazin formula:

< / BR>
in which R1is a hydrogen atom, halogen atom or optionally substituted lower alkyl group;

R2is optionally substituted paliperidone alkyl group or optionally substituted cycloalkyl group; X is an oxygen atom or S(O)pwhere p is an integer from 0 to 2;

Y is: (i) a group of the formula:

< / BR>
in which R3and R4independently are a hydrogen atom or optionally substituted lower alkyl group, or (ii) optionally substituted cycloalkanones group or optionally substituted cycloalkylcarbonyl group;

R5and R6independently are a hydrogen atom or optionally mixed with a lower alkyl group, or optionally substituted cycloalkyl group, or together with the adjacent nitrogen atom may form a nitrogen-containing heterocyclic group; m and n independently are an integer from 0 to 4, or its salt, a characteristic chemical stay alkyl group in 7-position, it was found that this compound, due to its unique chemical structure, unexpectedly exhibits excellent anti-allergic, anti-inflammatory, and also an inhibitory effect on platelet activating factor and eosinophil chemotaxis with excellent long-term effect and safety, and that it serves as an anti-asthmatic agent, because it suppresses bronchial spasm and dilatation, and as a prophylactic/therapeutic agent for allergic rhinitis and atopic dermatitis due to inhibitory effects on eosinophil chemotaxis. Based on these discoveries, the inventors carried out further research and created the present invention. Accordingly, the present invention relates to:

(1) the compound [I] or its salt,

(2) the compound described above in (1), where R1is a hydrogen or C1-6is an alkyl group,

(3) the compound described above in (1), where paliperidone alkyl group is a lower alkyl group having 2 or more carbon atoms,

(4) the compound described above in (3), where the lower alkyl group having 2 or more atoms pleased group of the formula:

< / BR>
in which R3aand R4aindependently are hydrogen or C1-6is an alkyl group,

(6) the compound described above in (1), where R5and R6independently are hydrogen or C1-6is an alkyl group,

(7) the compound described above in (1), R1is a hydrogen atom; R2is C2-6is an alkyl group;

X is an oxygen atom;

Y is a group of the formula:

< / BR>
in which R3band R4bindependently are C1-4is an alkyl group;

R5and R6independently are hydrogen or C1-6is an alkyl group; m and n independently are 1 or 2,

(8) the compound described above in (7), where R2is branched C3-6is an alkyl group,

(9) the compound described above in (8), where R5and R6are a hydrogen atom;

m and n are equal to 1,

(10) the compound described above in (8), where C3-6is an alkyl group is an isopropyl group,

(11) the compound described above in (8), where C3-6is an alkyl group is tert-butilkoi group

(12) the compound described above in (1), and is 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-is-dimethyl-3-sulfamoyl-1-propoxy)-7-n-propyl[1,2,4] - triazolo[1,5-b] pyridazine or its salt,

(14) the compound described above in (1), and is 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4] -triazolo [1,5-b]pyridazine or its salt,

(15) the compound described above in (1), and is 6- (2,2-diethyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4] - triazolo[1,5-b]pyridazine or its salt,

(16) the compound described above in (1), and is 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isobutyl[1,2,4] -triazolo [1,5-b]pyridazine or its salt,

(17) the compound described above in (1), and is 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-tert-butyl[1,2,4] - triazolo[1,5-b]pyridazine or its salt,

(18) the compound described above in (1), and is 6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-tert-butyl[1,2,4] -triazole [1,5-b]pyridazine or its salt,

(19) the method of obtaining the compounds described above in (1), including the interaction of the compounds of formula:

< / BR>
or its salt with the compound of the formula:

< / BR>
or its salt, where Z1and Z2are tsepliaeva group in the reaction of mutual exchange; other symbols are as described above in (1),

(20) the compound of the formula:

< / BR>
in which W is tsepliaeva group; the other symbols is icanoe above in (1),

(22) medicinal preparation, which comprises the compound described above in (1),

(23) the composition for the inhibition of platelet activating factor which comprises the compound described above in (1),

(24) a composition for inhibiting eosinophilic chemotaxis, which comprises the compound described above in (1),

(25) Antiasthmatic composition that includes a compound described above in (1),

(26) antiallergic composition that includes a compound described above in (1),

(27) the composition for prevention or treatment of allergic rhinitis, which comprises the compound described above in (1), and

(28) the composition for prevention or treatment of atopic dermatitis, which comprises the compound described above in (1).

In that case, if the compound [I] or its salt contains in its molecular structure asymmetric carbon atom, then the scope of the present invention is enabled optical isomers and racemic mixtures.

The term "lower alkyl" used in the present description, means, for example, linear or branched C1-6is an alkyl group. Examples of the above-mentioned "C1-6is an alkyl group" include methyl, ethyl, propyl, from the th in the present description, means, for example, C3-6-cycloalkyl group. Examples of the above-mentioned "C3-6-cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "paliperidone alkyl group" used in the present invention means, for example, alkyl group having two or more carbon atoms. Preferred examples mnogoukladnoi alkyl groups include linear or branched C2-6is an alkyl group (for example, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl), preferably a branched alkyl group (for example, isopropyl, isobutyl, tert-butyl).

Examples of substituents which do not necessarily have the above-mentioned "lower alkyl", "cycloalkyl group" and "paliperidone alkyl group include hydroxyl group, amino group, carboxyl group, nitro, mono - or di-lower alkylamino (for example, mono - or di-C1-6-alkylamino, such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino), low alkoxygroup (primer, C1-6-alkoxygroup, such as methoxy, ethoxy, propoxy, hexyloxy), low alkylcarboxylic, (for example, C1-6-alkili the number of substituents is from 1 to 4.

The term "halogen atom" used in the present invention means, for example, fluorine, chlorine, bromine, iodine.

The term "cycloalkenes group" used in the present invention means, for example, a divalent group obtained by removing two hydrogen atoms connected to two different carbon atoms 3-7-membered cycloalkane.

The term "cycloalkylcarbonyl group" used in the present description, means, for example, a divalent group obtained by removing two hydrogen atoms linked to the carbon atom 3-7-membered cycloalkane More specifically, examples cycloalkylation groups include the following:

preferably the following:

< / BR>
The term "nitrogen-containing heterocyclic group" used in the present invention means, for example, a group obtained by removing a hydrogen atom bound to the nitrogen atom 3-13-membered nitrogen-containing heterocyclic group which contains one nitrogen atom in addition to carbon atoms and which may contain 1 to 3 heteroatoms selected from atoms containing nitrogen atoms, oxygen atoms or sulfur atoms. More specifically, examples of the nitrogen-containing heterocyclic groups vklyuchayutsya optional has mentioned "cycloalkenes group", "cycloalkylcarbonyl group", and "nitrogen-containing heterocyclic group" may serve as the lower alkyl groups (for example, C1-6is an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl), an amino group, mono - or di-lower alkylamino (for example, mono - or di-C1-6-alkylamino, such as methylamino, ethylamino, dimethylamino, diethylamino), hydroxyl group, carboxyl group, nitro group, lower CNS group (for example, C1-6-CNS group, such as methoxy, ethoxy and propoxy) and halogen atoms (e.g. fluorine, chlorine, bromine, iodine), while the number of substituents is from 1 to 3.

In the above formulas, R1represents a hydrogen atom, halogen atom or optionally substituted lower alkyl group. As the "halogen atom", the "optionally substituted lower alkyl group, R1use such that the above-mentioned "halogen atom" and "optionally substituted lower alkyl group". Preferred examples of R1include a hydrogen atom, a C1-6-alkyl (e.g. methyl, ethyl, propyl, isopropyl), usually mainly use hydrogen atom.

In the above is but substituted cycloalkyl group. As the "optionally substituted paliperidone group", "optionally substituted cycloalkyl group" R2use those that are mentioned above for the "optionally substituted paliperidone alkyl group", "optionally substituted cycloalkyl group". Preferred examples of R2include branched C3-6is an alkyl group (for example, isopropyl, isobutyl, tert-butyl), mainly typically use ISO-propyl group, tert-boutelou group, most preferably ISO-propyl group.

In the above formulas, X represents an oxygen atom or S(O)pwhere p is an integer from 0 to 2. Preferred examples of X include an oxygen atom, S, is usually mainly use the oxygen atom.

In the above formulas, Y represents

(I) a group of the formula:

< / BR>
in which R3and R4independently represent a hydrogen atom or optionally substituted lower alkyl group, or

(II) optionally substituted cycloalkenyl group or optionally substituted cycloalkylcarbonyl group.

As the "optionally substituted lower alkyl" R3and R4"optional samestore mentioned above for the "optionally substituted lower alkyl" of the "optionally substituted cycloalkanones group" or "optionally substituted cycloalkylcarbonyl group".

II preferred examples of Y include groups of the formula:

< / BR>
in which R3aand R4aindependently represent a hydrogen atom or a C1-6is an alkyl group such as methyl, ethyl, propyl or isopropyl. More preferably typically use a group of the formula:

< / BR>
in which R3band R4bindependently represent C1-4is an alkyl group such as methyl or ethyl.

The preference for Y also give cycloalkenyl groups, or cycloalkylcarbonyl groups; more preferred examples cycloalkylation groups include the following:

< / BR>
the most preferred examples cycloalkylation groups include the following:

< / BR>
In the above formulas, R5and R6independently represent a hydrogen atom, optionally substituted lower alkyl group or optionally substituted cycloalkyl group, or together with the adjacent nitrogen atom may form a nitrogen-containing heterocyclic ring, which optionally is substituted. As the above-mentioned "optionally substituted lower alkyl group", "optionally substituted cycloalkyl group" R5and R6, "nitrogen-containing heterocyclic ring, m a nitrogen atom, use those that are mentioned above for the "optionally substituted lower alkyl group", "optionally substituted cycloalkyl groups, nitrogen-containing heterocyclic ring, which optionally is substituted". Preferred examples of R5and R6include hydrogen atoms and C1-6is an alkyl group (e.g. methyl, ethyl, propyl, isopropyl), mainly typically use hydrogen atoms.

In the above formulas, m represents an integer from 0 to 4. Preferably m is an integer from 1 to 4, usually m is 1 or 2.

In the above formulas, n represents an integer from 0 to 4. Preferably, n is an integer from 1 to 4, n is usually 1 or 2. Most preferably, m and n were equal to 1.

Preferred examples of compound [1] or its salts are the following:

connection, where R1is a hydrogen atom;

R2is C2-6is an alkyl group;

X is an oxygen atom;

Y is a group of the formula:

< / BR>
in which R3band R4bindependently are C1-4is an alkyl group; R5and R6are hydrogen or C1-6is an alkyl group[1] or its salts are the following:

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-ethyl[1,2,4]triazole [1,5-b]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-n-propyl[1,2,4] triazolo [1,5-b]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4] triazolo[1,5-b]pyridazin or its salt,

6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4] triazolo[1,5-b]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isobutyl[1,2,4] triazolo[1,5-b]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-tert-butyl[1,2,4] triazolo[1,5-b]pyridazin or its salt,

6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-tert-butyl[1,2,4] triazolo[1,5-b]pyridazin or its salt.

The salt of compound [1] of the present invention can be represented by the salts of inorganic acids (e.g. hydrochloric, phosphoric, Hydrobromic, sulfuric acid) and salts of organic acids (e.g. acetic, formic, propionic, fumaric, maleic, succinic, tartaric, citric, malic, oxalic, benzoic, methanesulfonic, benzosulfimide acid, preferably physiologically acceptable acid salts of accession. In the case that the compound [I] of the present invention is Deputy acid group, e.g. the metal, such as sodium, potassium, calcium or magnesium, or ammonia) or an organic base (for example, three-C1-3-alkylamine such as triethylamine).

Methods for obtaining compounds [I] of the present invention or its salts are described below.

The compound (I) of the present invention or its salt can be synthesized by method A, which are connected by the formula:

< / BR>
or its salt interacts with compounds of the formula:

< / BR>
where the symbols have the same meanings defined above, or its salt. Examples tseplyaesh groups Z1include halogen atoms (e.g. chlorine, bromine, iodine). C6-10-arylsulfonate, (for example, benzosulfimide, p-toluensulfonate) and C1-4-alkylsulfonates (for example, methanesulfonate).

The group Z2which when reacted with Z1it molecule can be represented by a hydrogen atom or an alkaline metal such as sodium and potassium, when X is an oxygen atom or a sulfur atom, or an alkaline metal such as sodium or potassium, when X is-SO - or-SO2. In this reaction, the compound (III] or its salt is usually used in an amount of from 1 to 5 moles, preferably from 1 to 2 malevizi Foundation. As an example, the base can be represented by an alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal alkoxides such as sodium methoxide and ethoxide sodium; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and carbonates such as sodium carbonate and potassium carbonate.

This reaction can also be accomplished in an inert solvent, examples of which may include alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons, such as benzene, toluene and xylene; NITRILES, such as acetonitrile; amides, e.g. dimethylformamide and dimethylacetamide; and sulfoxidov, for example, dimethyl sulfoxide.

The reaction temperature is usually in the range from 10 to 200oC, preferably from 50 to 100oC. the reaction time is usually from 30 minutes to 24 hours, preferably from 1 to 6 hours.

The compound [I] of the present invention or its salt can also be synthesized by the method (B), in which the compound of the formula:

< / BR>
in which the symbols have the same meanings defined above, or its salt interacts with the connection"ptx2">

In this reaction, the compound [V] or its salt is used usually at a content of 1 to 5 moles, preferably 1 to 2 moles per mole of the compound (IV) or its salt.

This condensation reaction is preferably carried out in the presence of a base. An example of a Foundation can serve as the alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methylate and sodium ethylate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and carbonates such as sodium carbonate and potassium carbonate.

This reaction can also be accomplished in an inert solvent, examples of which include alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxidov, such as dimethylsulfoxide.

The reaction temperature is usually in the range from 10 to 200oC, preferably from 50 to 150oC. the reaction Time is usually from 30 minutes to 24 hours, preferably from 1 to 10 hours.

The compound [I] of the present invention or its salt can be the controls group; other symbols have the same meaning defined above, or its salt interacts with the compound of the formula [VII]:

< / BR>
in which the symbols have the same meaning defined above, or its salt.

Examples tseplyaesh group W include halogen atoms (e.g. chlorine, bromine, iodine), C6-10-arylsulfonate (for example, benzosulfimide, p-toluensulfonate) and C1-4- alkylsulfonates (for example, methanesulfonate), preferably halogen atoms (e.g. chlorine, bromine, iodine).

In this reaction, the compound [VII] or its salt is used usually in an amount of from 1 to 5 moles, preferably 1 to 2 moles per mole of compound [VI] or its salt.

This reaction can be performed in an inert solvent, examples of which may include alcohols such as methanol and ethanol; ethers, such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxidov, such as dimethylsulfoxide.

The reaction temperature is usually from -20 to 100oC., preferably from -10 to 50oC. Time reaccount in free form, it can be converted in a known manner in salt. When the compound [I] obtained as a salt, it can be converted into a free form or another salt. The compound [I] or its salt thus obtained, can be extracted and cleaned by known methods, for example by excretia solvent, pH regulation, redistribution, salting out, crystallization, recrystallization and chromatography. When you get the compound [I] or its salt in a mixture of optical isomers, it can be divided into d - and L-configuration of the conventional optical resolution.

Further describes methods of obtaining the starting compounds [II], [III], [IV] , [V] , [VI] and [VII] or their salts, which can be used to obtain the compound [I] or its salt.

Salts of these compounds include the salts of inorganic acids (e.g. hydrochloric, phosphoric, Hydrobromic, sulfuric acid) and salts of organic acids (e.g. acetic, formic, propionic, fumaric, maleic, succinic, tartaric, citric, malic, oxalic, benzoic, methanesulfonic, benzosulfimide acid). If these connections Deputy acidic group such as-COOH, it can form a salt with Neorganicheskie, or ammonia) or an organic base (for example three-C1-3-alkylamine such as triethylamine).

The original compound [II] or its salt can be synthesized, for example, by the method described in "Journal of Organic Chemistry, vol.39, p. 2143 (1974) or a modification of this method.

The original compound [III] or its salt or the compound (V) or its salt can be synthesized, for example, by the methods described in Chemische Berichte, Vol. 91, p 2130 (1958), Jourmal of Organic Chemistry, Vol. 52, p.2162 (1987) and EP 381132/1990, or modifications of them

The original compound (IV) or its salt can be synthesized, for example, by the method described in EP 381132/1990 or its modification.

The original compound (VI) or its salt can be synthesized, for example, by (1) the interaction of compound [II] or its salt with the compound of the formula:

Z2X-(CH2)m-Y-(CH2)n- SO2W, (VIII)

where the symbols have the same meaning defined above, or (2) the interaction of the compound (IV) or its salt with the compound of the formula:

Z1-(CH2)m-Y-(CH2)n- SO2W, (IX)

in which the symbols have the same value, which is defined above.

In the above reactions (1) the compound [VIII] is used usually in number of the out in the same manner, as described above, the reaction of the compound [II] or its salt and the compound [III] or its salt.

In the above reaction (2) compound [IX] is used usually in an amount of from 1 to 5 moles, preferably 1 to 2 moles per mole of compound [IV] or its salt. This reaction can be performed in the same manner as above described the reaction of the compound [IV] or its salt and the compound [V] or its salt.

The original compound [VII] or its salt and the parent compound [VIII] and [IX] can usually be synthesized by known methods or their modifications.

Although salts which can be formed by the above-described starting compounds, are not subject to restrictions until I accomplish the purpose of the present invention, examples of salts include the same salts as those described above and which can be formed using the compound [I].

Although these initial compounds or their salts, thus obtained, can be extracted and cleaned by known methods such as solvent extraction, pH regulation, redistribution, salting out, crystallization, recrystallization and chromatography, can be used as starting materials for the next% the reactions for the synthesis of the above desirable compounds, has as substituents of the amino group, carboxyl group or hydroxyl group, these substituents may have a protective group commonly used in the chemistry of peptides and so on ; the desired compound can be obtained by removing the protective group after the reaction.

Protective groups for amino include, for example, formyl, C1-6-alkylcarboxylic group (for example, acetyl, ethylcarbazole), phenylcarbonylamino group, C1-6-allyloxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl), vinyloxycarbonyl group, C7-10-aralkylamines group (for example, benzylcarbamoyl), trityloxy group, palolo group and N,N-dimethylaminomethylene group, which optionally are substituted. Examples of substituents which do not necessarily have these groups include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6-acylcarnitine group (for example, methylcarbamyl, ethylcarbodiimide, butylcellosolve) and nitro group, and the number of substituents is from 1 to 3.

Examples of protective groups for the carboxyl group include C1-6is an alkyl group (e.g. methyl, ethyl, the part replaced. Examples of substituents which do not necessarily have these groups include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), formyl, C1-6- acylcarnitine group (for example, acetyl, ethylcarbitol, butylcarbamoyl) and nitro group, and the number of substituents is from 1 to 3.

Examples of protective groups for the hydroxyl group include C1-6is an alkyl group (e.g. methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, tert-boutelou), phenyl, C7-10-kalkilya group (e.g., benzyl), formyl, C1-6-acylcarnitine group (for example, acetyl, ethylcarbazole), vinyloxycarbonyloxy, benzoyloxy, C7-10-aralkylamines group (for example, benzylcarbamoyl), pyranyloxy, fornillo and silyl, which are not necessarily replaced. Examples of substituents which do not necessarily have these groups include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6is an alkyl group (e.g. methyl, ethyl, n-sawn), phenyl, C7-10- kalkilya group (e.g. benzyl) and nitro group, and the number of substituents is from 1 to 4.

The protective group can be removed on the guides, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium-fluoride, palladium acetate, etc.

The compound [I] or its salt of the present invention can be safely used as anti-asthma drugs in mammals (e.g. humans, mice, dogs, rabbits, oxen), because they exhibit excellent anti-allergic, anti-inflammatory effect and an inhibitory effect on platelet activating factor and eosinophil chemotaxis with low toxicity (acute toxicity LD50>2 kg/kg). The compound (I) or its salt inhibit eosinophil chemotaxis and local eosinophilic infiltration in allergic and inflammatory reactions. Therefore, it is suitable as a therapeutic agent for diseases associated with eosinophilic infiltration. More specifically, it can be used to treat or prevent eosinophilic diseases in the above-mentioned mammals, including allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis and hypertensive pneumonia; skin disease such as eczema, herpetic dermatitis and psoriasis;funds may be oral or neuroretinal.

The drug of the present invention may contain as pharmaceutical components other active ingredients than the compound [I] or its salt (for example, anti-asthmatic, anti-allergic, anti-inflammatory, antimicrobial and antifungal agents). Examples of such pharmaceutical ingredients include anti-asthma drugs (e.g., theophylline, procaterol, ketotifen, terfenadine, azelastin, seratrodast), an antiallergic drug (ketotifen, terfenadine, azelastin, epinasty), anti-inflammatory agents (for example, nutritional, ibuprofen, indomethacin), antimicrobial agents (e.g., cefixime, cefdinir, ofloxacin, tosufloxacin), antifungal agents (e.g., fluconazole, Itraconazole). These components are not subject to restrictions up until I accomplish the purpose of this invention, and may be used by mixing in an appropriate state. Suitable dosage forms include tablets (including tablets coated with sugar and tablets, film-coated), pills, capsules (including microcapsules), granules, powders, syrups, emulsions, suspensions, injectables, pharmaceutical forms for inhalation and Masia of Japan). The content of compound [1] or its salt with drugs of the present invention varies depending on the form of the drug and it usually ranges from 0.01 to 100 weight. %, preferably from 0.1 to 50 wt.%, more preferably from 0.5 to 20 wt.% relative to the total weight of the medicinal product.

More specifically, the tablets can be obtained by granulating a pharmaceutical preparation in the form as it is or in a homogeneous mixture with fillers, binders, disintegrators and other appropriate additives, using a suitable method, then add lubricants, etc., and by molding the mixture by extrusion or by a direct molding by pressing a pharmaceutical preparation in the form as it is or in a homogeneous mixture with fillers, binders, disintegrators and other appropriate additives, or by molding the pre-pressing the obtained granules as they are or in a homogeneous mixture with suitable additives These pills may include, when necessary, dyes, neutralizing means, etc., and can be covered by a coating.

Preparations for injection can be obtained by dissolving, spendelove or e is designated for injection, physiological saline or ringer's solution or nonaqueous solvent, such as vegetable oil, and diluting to a given number, or transfer a given amount of a pharmaceutical preparation in vials for injection and sealing ampoules.

Suitable carriers for oral drugs include substances that are usually used in obtaining pharmaceutical drugs, such as starch, mannitol, crystalline cellulose and sodium carboxymethyl cellulose. Suitable carriers for drugs for injection include distilled water, physiological saline, glucose solutions and the solutions for intravenous infusion. When necessary, may be added other additives commonly used in the manufacture of pharmaceutical products.

Depending on the patient's age, body weight, symptoms, method of administration, medication, frequency of administration and other factors, the daily dose of these drugs is usually from 0.1 to 100 mg/kg, preferably from 1 to 50 mg/kg and more preferably from 1 to 10 mg/kg, calculated on the daily dose of the active ingredient (the compound [I] or its salt), which is injected in the form of one or two preteenie will be further described in more detail by the subsequent working examples, reference examples, preparation examples and experimental examples, which should not be construed as limiting the invention.

The following working examples, the fraction containing the desired product were discovered through research carried out using TLC (thin layer chromatography). TLC was carried out on the plate Merck 60F254using UV detector.

REFERENTIAL EXAMPLE 1.

GETTING 3,6-DICHLORO-4-ETHYLPYRIDINE.

To a suspension consisting of 22.5 g of 3,6-dichloropyridazine, 12.7 g of silver nitrate and 16.3 g of propionic acid in 250 ml of water, was added a solution of 49.3 g of sulfuric acid in 250 ml of water at 50oC, then for 20 minutes at 60oC added 93 g peroxodisulfate of ammonia in 200 ml of water. The reaction mixture was heated for 30 minutes at a temperature of from 70 to 75oC. After cooling, using a 25% solution of ammonium hydroxide established pH of the reaction mixture is 7 and was extracted with ethyl ether. The extract was washed with water, dried (MgSO4and under reduced pressure drove the solvent. The residue was purified silicagel column chromatography, receiving 13.5 g of the named compound.

NMR (CDClPYRIDAZINE.

To obtain 12.7 g of the named compound, using 16.6 g 3.6-dichloropyridazine and 14.4 g of n-butyric acid, was carried out the same reaction as in reference example 2.

NMR (CDCl3) : 1.10 (3H, t, J = 7 Hz), 1.5-1.9 (2H, m), 2.72 (2Ht, J = 7 Hz), 7.37 (1H, s).

REFERENCE EXAMPLE 3.

GETTING 3.6-DICHLORO-4-ISOBUTYLPYRAZINE.

To obtain 15.0 g of the titled compounds via 22.3 g 3.6-dichloropyridazine and 19.9 g of isovalerianic acid, carried out the same reaction as in reference example 1.

NMR (CDCl3) : 1.06 (6H, d, J=7 Hz), 1.8-2.2 (1H, m), 2.60 (2H, d, J=7 Hz), 7.38 (1H, s).

REFERENCE EXAMPLE 4.

GETTING 3,6-DICHLORO-4-H-HEXYLPYRIDINE.

To obtain 14.4 g of the named compound, using 11.7 g 3.6-dichloro-pyridazine and 23 g of n-heptane acid, carried out the same reaction as in reference example 1.

NMR (CDCl3) : 0.84-9.97 (3H, m), 1.22-1-48 (8H, m); of 1.57 - 1.76 (2H, m), 7.37 (1H, s).

REFERENCE EXAMPLE 5.

GETTING 4-CYCLOPENTYL-3,6-DICHLOROPYRIDAZINE.

To obtain 28.7 g of the named compound, using 22.4 g 3.6-dichloro-pyridazine and 25.1 g cyclopentanecarbonyl acid, carried out the same reaction as in reference example 1.

NMR (CDCl3) x2">

A mixture of 13.5 g 3.6-dichloro-4-ethylpyridine in 150 ml of 25% ammonium hydroxide solution and 10 ml of ethanol was heated in a sealed tube for 22 hours at a temperature of from 130 to 140oC. After cooling, the solvent was distilled. To the residue was added water and the resulting crystals were collected by filtration and dromio water and ethyl ether, while 6.96 g of the named compound.

NMR (d6DMSO) : 1.16 (3H, t, J=7 Hz), 2.54 (2H, g, J=7 Hz), 6.48 (2H, s), 6.73 (1H, s).

REFERENCE EXAMPLE 7.

OBTAIN 3-AMINO-6-CHLORO-5-H-PROPYLPYRIDINE.

To obtain 6.8 g of the named compound, using 12.7 g 3.6-dichloro-5-n-propylpyridine, 150 ml of 25% solution of ammonium chloride and 5 ml of ethanol was carried out the same reaction as in reference example 6.

NMR (CDCl3) : 1.00 (3H, t, J=7 Hz), 1.57-1.76 (2H, m), 2.59 (2H, t, J=7 Hz), 4.80 (2H, br, s), 6.60 (1H, s).

REFERENCE EXAMPLE 8.

OBTAIN 3-AMINO-6-CHLORO-5-ISO-PROPYLPYRIDINE.

To obtain 11.1 g of the titled compounds via 21.7 g 3.6-dichloro-4-isopropylpyridine, 170 ml of 25% ammonium hydroxide solution and 10 ml of ethanol was carried out the same reaction as in reference example 6.

Melting point: 164-165oC.

NMR (CDCl3

To obtain 7.3 g of the named compound, using 15.0 g 3.6-dichloro-4-isobutylpyrazine, 180 ml of 25% ammonium hydroxide solution and 5 ml of ethanol was carried out the same reaction as in reference example 6.

Melting point: 122-123oC.

NMR (CDCl3) : 0.96 (6H, d, J=7 Hz), 1.8-2-2(1H, m), 2.48 (2H, d, J=7 Hz), 4.88 (2H, br, s), 6.38 (1H, s).

REFERENCE EXAMPLE 10.

OBTAIN 3-AMINO-5-TERT-BUTYL-6-CHLOROPYRIDAZINE.

To obtain 20.8 g of the titled compounds via 31.1 g of 4-tert-butyl-3.6-dichloropyridazine, 150 ml of 25% ammonium hydroxide solution and 15 ml of ethanol was carried out the same reaction as in reference example 6.

Melting point: 185-188oC.

NMR (CDCl3) : 1.44 (9H, s), 4.88 (2H, br, s), 6.74 (1H, s).

REFERENCE EXAMPLE 11.

OBTAIN 3-AMINO-6-CHLORO-5-H-HEXYLPYRIDINE.

To obtain 6.2 g of the above connections using 14.4 g 3.6-dichloro-4-n-hexylpyridine, 150 ml of 25% ammonium hydroxide solution and 150 ml of ethanol was carried out the same reaction as in reference example 6.

Melting point: 97-98oC.

NMR (CDCl3) : 0.84-1.02 (3H, m), 1.20-1.48 (8H, m), 1.54-1.71 (2H, m), 4.97 (2H, br, s), 6.62 (1H, s).

REFERENTIAL EXAMPLE 12.

PO 28.7 g of 4-cyclo-pentyl-3.6-dichloro-pyridazine, 210 ml of 25% ammonium hydroxide solution and 70 ml of ethanol was carried out the same reaction as in reference example 6.

NMR (CDCl3) : 1.4-2.3 (8H, m), 3.20 (1H, m), 4.84 (2H, br, s), 6.65 (1H, s).

REFERENCE EXAMPLE 13.

GETTING OXIME H-(6-CHLORO-5-ETHYLPYRIDINE-3-YL)FORMAMIDE.

To a suspension of 4.6 g of 3-amino-6-chloro-5-ethylpyridine in 58 ml of toluene was added 6.2 ml of dimethylformamidine and the reaction mixture was heated in a flask under reflux for 2 hours. Under reduced pressure drove the solvent. The residue was purified silicagel column chromatography using ethyl acetate-methanol (at a ratio of 10:1) was carried out by elution. The fractions containing the target compound were combined and concentrated. The residue was dissolved in methanol (40 ml), to the solution was added 1.8 g of hydroxylaminopurine and mixed at room temperature for 2 hours. The obtained crystals were collected by filtration and washed with a small amount of methanol, receiving 4.40 g of the named compound.

Melting point: 175-178oC.

Elementary analysis for C7H9N4OCl:

Calculated (%): C, 41.91; H, 4.52; N, 27.93.

Found (Percent): C, 41.73; H, 4.65; N, 27.69.

NMR (d6-DMSO) : 0.95 (3H, t, J=7 Hz), 1.5-1.8 (2H, m), 2.57 (2H, t, J=7 Hz), 7.36 (1H, s), 7.91 (1H, d, j=10 Hz), 9.65 (1H, d, J= 10 Hz), the 10.40 (1H, s).

REFERENCE EXAMPLE 15.

GETTING OXIME N-6(CHLORO-5-ISOPROPYLPYRIDINE-3-YL)FORMAMIDE.

To obtain 10.6 g of the named compound, using 8.6 g of 3-amino-6-chloro-5-isopropylpyridine, carried out the same reaction as in reference example 13.

Melting point: 170-171oC.

Elementary analysis for C8H11N4OCl:

Calculated (%) C, 44.76; H, 5.17; N, 26.10.

Found (Percent): C, 44.62; H, 5.02; N, 26.01.

REFERENCE EXAMPLE 16.

GETTING OXIME N-(6-CHLORO-5-ISOBUTYLPYRAZINE-3-YL)FORMAMIDE.

To obtain 4.9 g of the named compound, using 7.0 g of 3-amino-6-chloro-5-isobutylpyrazine, carried out the same reaction as in reference example 13.

Melting point: 155-158oC.

Elementary analysis for C9H13N4OClH2O:

Calculated (%): C, 43.82; H, 6.13; N, 22.71.

Found (Percent): C, 43.23; H, 6.21; N, 23.00.

REFERENCE EXAMPLE 17.

GETTING OXIME N-(5-TERT-BUTYL-6-X the-butyl-6-chloropyridazine, carried out the same reaction as in reference example 13.

Melting point: 221-224oC.

Elementary analysis for C9H13N4OCl:

Calculated (%): C, At 47.27; H, 5.73; N, 24.50.

Found (Percent): C, 47.10; H, 5.48; N; 24.68.

REFERENCE EXAMPLE 18.

GETTING OXIME N-(6-CHLORO-5-H-HEXYLPYRIDINE-3-YL)FORMAMIDE.

To obtain 5.7 g of the named compound, using 6.0 g of 3-amino-6-chloro-5-n-hexylpyridine, carried out the same reaction as in reference example 13.

Melting point: 131-133oC.

Elementary analysis for C11H17N4OCl:

Calculated (%): C, 51.46; H, 6.67; N, 21.82.

Found (Percent): C, 51.15; H, 6.87; N, 21.59.

REFERENCE EXAMPLE 19.

GETTING OXIME N-(6-CHLORO-5-CYCLOPENTENOPYRIDINE-3-YL)FORMAMIDE.

To obtain 8.05 g of the named compound, using 8.9 g of 3-amino-6-chloro-5-cyclopentenopyridine, carried out the same reaction as in reference example 13.

Melting point: 207-208oC.

Elementary analysis for C10H13N4OCl:

Calculated (%): C, 49.90; H, 5.44; N, At 23.28.

Found (Percent): C, 49.85; H, 5.60; N, 23.31.

REFERENCE EXAMPLE 20.

RECEIVED the oC heated the mixture was 4.02 g of the oxime N-(6-chloro-5-ethylpyridine - 3-yl)formamide and 25 g of polyphosphoric acid. After cooling, the reaction mixture was poured into a mixture of ice water and was extracted with dichloromethane. The extract was washed with water and dried (MgSO4and then under reduced pressure drove the solvent. To the residue was added hexane and the resulting crystals were collected by filtration, receiving of 2.33 g of the named compound.

Melting point: 84-85oC.

Elementary analysis for C7H7ClN4:

Calculated (%): C, 46.04; H, 3.86; N, At 30.68.

Found (Percent): C, 46.00; H, 3.76; N, 30.59.

REFERENCE EXAMPLE 21.

GETTING OXIME 6-CHLORO-7-H-PROPYL[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

To obtain 3.1 g of the named compound, using 4.7 g of the oxime N-(6-chloro-5-n-propylpyridine-3-yl)formamide and 23 g of polyphosphoric acid was carried out the same reaction as in reference example 20.

Melting point: 61-62oC.

Elementary analysis for C8H9ClN4:

Calculated (%): C, 48.87; H, 4.61; N, 28.49.

Found (Percent): C, 48,87; H, 4,55; N, 28.55.

REFERENCE EXAMPLE 22.

OBTAINING 6-CHLORO-7-ISOPROPYL[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE

To polyphosphoric acid, carried out the same reaction as in reference example 20.

Melting point: 53-54oC.

Elementary analysis for C8H9ClN4:

Calculated (%): C, 48.87; H, 4.61; N, 28.49.

Found (Percent): C, 48.85; H, 4.55; N, 28.48.

REFERENCE EXAMPLE 23.

OBTAINING 6-CHLORO-7-ISOBUTYL[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

To obtain 2.2 g of the named compound, using 4.6 g of the oxime N-(6-chloro-5-isobutylpyrazine-3-yl)formamide and 22 g of polyphosphoric acid was carried out the same reaction as in reference example 20.

Melting point: 60-62oC.

Elementary analysis for C9H11ClN4:

Calculated (%): C, 51.31; H, 5.26; N, 26.60.

Found (Percent): C, 51.33; H, 5.05; N, 26.71.

REFERENCE EXAMPLE 24.

GETTING 7-TERT-BUTYL-6-CHLORO[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

To get to 5.13 g of the named compound, using 8.0 g of the oxime N-(5-tert-butyl-6-chloropyridin-3-yl)formamide and 38 g of polyphosphoric acid was carried out the same reaction as in reference example 20.

Melting point: 110-112oC.

Elementary analysis for C9H11ClN4:

Calculated(%): C, 51.31; H, 5.26; N, 26.60.

Found (percent): C, the A.

To obtain 2.2 g of the named compound, using 5.5 g of the oxime N-(6-chloro-5-n-hexylpyridine-3-yl)formamide and 22 g of polyphosphoric acid was carried out the same reaction as in reference example 20.

Melting point: 52-53oC.

Elementary analysis for C11H15ClN4:

Calculated(%): C, 55.35; H, 6.33; N, 23.47.

Found (Percent): C, 55.25; H, 6.12; N, 23.52.

REFERENCE EXAMPLE 26.

OBTAINING 6-CHLORO-7-CYCLOPENTYL[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

To obtain the 5.51 g of the named compound, using 7.76 g of the oxime N-(6-chloro-5-cyclopentenopyridine-3-yl)formamide and 40 g of polyphosphoric acid was carried out the same reaction as in reference example 20.

Melting point: 57-59oC.

Elementary analysis for C10H11ClN4:

Calculated(%): C, 53.94; H, 4.98; N, 25.16.

Found (Percent): C, 53.88; H, 4.97; N, 25.07.

REFERENCE EXAMPLE 27.

GETTING OXIME N-(6-CHLORO-5-ISOPROPYLPYRIDINE-3-YL)NDIMETHYLACETAMIDE

In 40 ml of toluene added 3.44 g of 3-amino-6-chloro-5 - isopropylpyridine; added 4.44 g dimethylethylenediamine, then for 2 hours was carried out by heating in a flask with reflux condenser. After that, the mixture CoII and suirable with ethyl acetate. The desired fraction was collected and concentrated, the obtained residue was dissolved in 25 ml of methanol; added 1.37 g of hydroxylaminopurine, then for 1 hour was carried out by stirring at room temperature. Formed crystals were collected by filtration, yield the named compound was 3.42,

Melting point: 175-178oC.

Elementary analysis for C9H13N4OCl:

Calculated (%): C, At 47.27; H, 5.73; N, 24.50.

Found (Percent): C, 47.21; H, 5.81; N, 24.21.

REFERENCE EXAMPLE 28.

OBTAINING 6-CHLORO-7-ISOPROPYL-2-METHYL[1,2,4,]TRIAZOLO(1,5-b]PYRIDAZINE.

At room temperature, thoroughly mixed 1.7 g of the oxime N-(6-chloro-5-isopropylpyridine-3-yl)ndimethylacetamide and 10 g of polyphosphoric acid, and then in an oil bath at 110-115oC for 1 hour there was a reaction. After that, the reaction mixture is cooled, added to the mixture with ice water, then carried out the extraction with dichloromethane. The extract was washed with water and dried over magnesium sulfate. After that, the extract was concentrated under reduced pressure, to the residue was added hexane, and the resulting crystals were collected by filtration, yield the named compound was 1.06 g

Melting point: 58-60o

EXAMPLE 1.

GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-ETHYL[1,2,4] TRIAZOLO[1,5-b]PYRIDAZINE

To a solution of 0.836 g of 3-hydroxy-2,2-DIMETHYLPROPANE-1-sulfonamida in 25 ml of tetrahydrofuran was added 0.42 g of 60% sodium hydride in oil and the mixture for 40 minutes, heated in a flask with reflux condenser. After cooling, to the reaction mixture was added 0.913 g of 6-chloro-7 - ethyl[1,2,4]triazolo [1,5-b]pyridazine and the mixture was heated in a flask under reflux with stirring for 2 hours. After cooling, the reaction mixture is poured into water, 1N hydrochloric acid was established pH 6, and extracted with ethyl acetate-tetrahydrofuran (at a ratio in a mixture 1:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4and under reduced pressure drove the solvent. The residue was purified silicagel column chromatography and then realized elution with dichloromethane-ethyl acetate-methanol (at a ratio of 10:10:1. Collected fractions containing the target compound, and the obtained crystals were recrystallize from a mixture of acetone and water, got 0.787 g of the named compound.

Melting point: 222-224oC

An elementary, 20.33.

EXAMPLE 2.

GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-H - PROPYL[1,2,4] TRIAZOLO[1,5-b]PYRIDAZINE.

To obtain 0.77 g of the named compound, using 0.90 g of 3-hydroxy-2,2-dimethyl-1-propanesulfinamide and 1.0 g of 6-chloro-7-n - propyl[1,2,4]triazolo[1,5-b]pyridazine, carried out the same reaction as in example 1.

Melting point: 196-198oC

Elementary analysis for C13H21N5O3S H2O:

Calculated (%): C, 45.20; H, 6.70; N, 20.27.

Found (Percent): C, 45.68; H, 6.39; N, 20.55.

EXAMPLE 3.

GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-ISO - PROPYL[1,2,4] TRIAZOLO[1,5-b]PYRIDAZINE.

To a solution of 0.669 g of 3-hydroxy-2,2-dimethyl-1-propanesulfinamide in 30 ml of tetrahydrofuran was added 0.336 g of 60% sodium hydride in oil and the mixture for 1 hour and heated in a flask with reflux condenser. After cooling, to the reaction mixture was added 0.748 g of 6-chloro-7-isopropyl[1,2,4]triazolo[1,5-b] pyridazine and the mixture was heated with stirring in a flask under reflux for 4 hours. After cooling, the reaction mixture was poured into a mixture of water, with ice, IN hydrochloric acid has established a pH of 6, and were extracted with ethyl acetate-tetrahydrofuran (if spumigena pressure drove the solvent. The residue was purified silicagel column chromatography and then realized elution with dichloromethane - ethyl acetate-methanol (at a ratio of 10:10:1). Combined fractions containing the target compound, and the obtained crystals were recrystallize from acetone-water, got a 110 g of the named compound. So pl. 197-198oC.

Elementary analysis for C13H21N5O3S:

Calculated (%): C, 47.69; H, 6.46; N, 21.39.

Found (Percent): C, 47.84; H, 6.60; N, At 21.33.

EXAMPLE 4.

GETTING 6-(2,2-DIETHYL-3-SULFAMOYL-1-PROPOXY)-7-ISOPROPYL[1,2,4]TRIAZOLO(1,5-b]PYRIDAZINE.

To obtain 0.967 g of the named compound, using 0.586 g of 3-hydroxy-2,2-diethylpropane-1-sulfonamida and 0.561 g of 6-chloro-7-n - isopropyl[1.2.4] triazolo[1,5-b] pyridazine, carried out the same reaction as in example 1.

Melting point: 190-192oC

Elementary analysis for C15H22N5O3S:

Calculated (%): C, 50.68; H, 7.09; N, 19.70.

Found (Percent): C, 50.90; H, 7.30; N, 19.42.

EXAMPLE 5.

GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-ISOBUTYL (1.2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

To obtain 0.63 g of the named compound, using 0.84 g of 3-hydroxy-2,2-dimetyl the example 1.

Melting point: 132-135oC

Elementary analysis for C14H23N5O3S H2O:

Calculated (%): C, 46.78; H, 6.45; N, 19.98.

Found (Percent): C, 46.91; H, 6.40; N, 19.79.

EXAMPLE 6. GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-TERT - BUTYL[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

To obtain 1.13 g of the named compound, using 1.0 g of 3-hydroxy-2,2-DIMETHYLPROPANE-1-sulfonamida and 1.2 g of 7-tert-butyl-6 - chloro-1.2,4]triazolo [1.5-b]pyridazine, carried out the same reaction as in example 1.

Melting point: 168-170oC

Elementary analysis for C14H23N5O3S:

Calculated (%): C, 49.25; H, 6.79; N, 20.51.

Found (Percent): C, 49.12; H, 6.69; N, 20.81.

EXAMPLE 7.

GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-H - HEXYL[1,2,4]TRIAZOLO[1.5-b]PYRIDAZINE.

To obtain 1.5 g of the named compound, using 0.74 g of 3-hydroxy-2,2-DIMETHYLPROPANE-1-sulfonamida and 1.0 g of 6-chloro-7-n-hexyl[1,2,4]triazolo[1.5-b] pyridazine, carried out the same reaction as in example 1.

Melting point: 150-151oC

Elementary analysis for C16H27N5O3S:

Calculated (%): C, 52.01; H, 7.37; N, 18.95

Found (Percent): C, 52.00; H, 7.32; N, 19.15.

To obtain 1.56 g of the named compound, using 1.01 g of 3-hydroxy-2.2-DIMETHYLPROPANE-1-sulfonamida and 1.27 g of 6-chloro-7 - cyclopentyl[1.2,4] triazolo[1,5-b] pyridazine, carried out the same reaction as in example 1.

Melting point: 170-172oC

Elementary analysis for C15H23N5O3S 0.5 H2O;

Calculated (%): C, 49.71; H, 6.67; N, 19.32.

Found (Percent): C, 49.65; H, 6.69; N 19.48.

EXAMPLE 9.

GETTING 7-ISOPROPYL-6-(3-SULFAMOYL-1-PROPOXY)[1,2,4]TRIAZOLO [1,5-b] PYRIDAZINE.

168 mg of 60% oily sodium hydride suspended in 25 ml of tetrahydrofuran; added 279 mg of 3-hydroxypropan-1-sulfonamida, then for 40 minutes was carried out by heating in a flask with reflux condenser. The mixture is then cooled, added 394 mg of 6-chloro-7-isopropyl[1,2,4]triazolo[1,5-b] pyridazine, then for 20 hours at room temperature was carried out by stirring. Then added a mixture of water with ice, 5N hydrochloric acid to set the pH of the mixture equal to 5. After this, the solution was saturated with sodium chloride and extracted with tetrahydrofuran; the extract was washed with saturated saline and dried over magnesium sulfate. Then the dried product was concentrated under the sustainable while 414 mg of the named compound.

Melting point: 190-191oC

Elementary analysis for C11H17N5O3S:

Calculated (%): C, 44.14; H, 5.72; N, At 23.39.

Found (Percent): C, Is 44.12; H, 5.77; N, 22.92.

EXAMPLE 10.

GETTING 6-(2,2-DIMETHYL-3-SULFAMOYL-1-PROPOXY)-7-ISO-PROPYL - 2-METHYL[1,2,4]TRIAZOLO[1,5-b]PYRIDAZINE.

In 30 ml of tetrahydrofuran suspended 252 mg of 60% oily sodium hydride; added 527 mg of 3-hydroxy-2,2-DIMETHYLPROPANE-1 - sulfonamida, then for 1 hour was carried out by heating in a flask with reflux condenser. After that, the mixture was cooled, added 632 mg of 6-chloro-7-isopropyl-2-methyl[1,2,4] triazolo[1,5-b]pyridazine, then carried out the heating in a flask under reflux for 6 hours. After that, the mixture was cooled, added to the mixture with ice water, to the mixture to bring its pH to 5 was added 5N hydrochloric acid. Then the solution was saturated with sodium chloride and extracted with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saturated saline and dried over magnesium sulfate. After that, the extract was concentrated under reduced pressure, the obtained residue was subjected to silicagel column chromatography and was suirable dichloromethane-ethyl acetate-IU the% of ethanol, this was 746 mg of the named compound.

Melting point: 196 to 199oC

Elementary analysis for C14H23N5O3S:

Calculated (%): C, 49.25; H, 6.79; N, 20.51.

Found (%) C, 49.18; H, 6.76; N, 20.44.

EXAMPLE 11.

GETTING 6-(2,2-DIETHYL-3-SULFAMOYL-1-PROPOXY)-7-TERT-BUTYL [1,2,4] TRIAZOLO[1.5-b]PYRIDAZINE.

In 30 ml of tetrahydrofuran added 380 mg of 60% oily sodium hydride; added 980 mg of 3-hydroxy-2,2 - diethylpropane-1-sulfonamida, then for 1 hour was carried out by heating in a flask with reflux condenser. After that, the mixture was cooled, added 1.0 g of 7-tert-butyl-6-chloro[1,2,4]triazolo[1,5-b]pyridazine, then carried out the heating in a flask under reflux for 3 hours. After that, the mixture was cooled, added to the mixture with ice water, then 5N hydrochloric acid to set the pH of the mixture equal to 4. After this, the solution was saturated with sodium chloride and extracted with tetrahydrofuran; the extract was washed with saturated saline and dried over magnesium sulfate. Then the extract was concentrated under reduced pressure, the obtained residue was purified silicagel column chromatography and was suirable dichloromethane-methanol (with whom the atur melting point: 172-174oC

Elementary analysis for C16H27N5O3S:

Calculated (%): C, 51.01; H, 7.37; N, 18.95.

Found (Percent): C, 51.86; H, 7.31; N, 18.90.

EXPERIMENTAL EXAMPLE 1

Below shows the results of pharmacological tests of the compounds [I] or salts thereof in accordance with the invention.

IMPACT ON BRONCHOSTENOSIS IN GUINEA PIGS CAUSED BY PLATELET ACTIVATING FACTOR (PAF).

Used Guinea pigs male Hartley (Hartley) (body weight about 500 g). Bronchostenosis in Guinea pigs caused by PAF (platelet activating factor) (1 µg/kg, intravenously) was measured in accordance with the method Consetta-Rosslare. Fixed a Guinea pig, in the supine position, analizirovali with urethane (1.5 g/kg, intravenously) with the use of tracheotomy, and the trachea was connected to the respirator through the cannula. The lateral branch of the tracheal cannula was attached to bronchomalacia (Model 7020, Ugobasile). Excess volume released air registered through bronchogenic on rectigraph (Rechte - Hori - 8S, San-ei Sokki). After the Guinea pig received Gallatin (1 mg/kg, intravenously), it was treated with PAF (1 µg/kg). One hour before treatment PAF her oral introduced medicine, sospendere 1.

From table 1 it follows that the desired compound [I] or its salt of the present invention has a greater inhibitory effect than the inhibitory effect of compounds having a 7-position with triazolopyridazines patterns methyl group.

EXPERIMENTAL EXAMPLE 2.

1) Preparation of eosinophil suspension of Guinea pigs.

Guinea pigs male Hartley (Hartley) (body weight about Z00 g) were treated intraperitoneally with 2 ml of horse serum (Whittaker Bioproducts) (Whittaker Bioproducts) once a week for 8 consecutive weeks. 48 hours after the last treatment in the peritoneal cavity is poured 75 ml of physiological saline solution lavage was collected and subjected to centrifugation at 400G (1500 rpm) for 5 minutes. The precipitate after centrifugation suspended in 5 ml of suspension Percoll (Percoll) that has uneven density (relative density d= 1.07), gradients caused on the upper surface of suspensions of Percoll (relative density d= 1.112: 5 ml, d=1.095 has:10 ml, d=1.090:10 ml, d=1.085:7 ml) and subjected to centrifugation (18oC) when 1000oC (2200 rpm) for 30 minutes. Gathered layer of cells formed in the boundary area between d= und) to remove impurities, contaminating erythrocytes.

The precipitate three times washed with a solution of Hanks (Hanks), containing 10 mm Hepes (Dojin KAGAKU) (Called Dojin) (Hanks-Hepes) and suspended in Hanks-Hepes containing 2% (wt./about.) serum albumin human (Waco, Pure Chemical) (Wako Pure Chemical) (Hanks - Hepes - HSA) at a concentration of 5.56106cells/ml Eosinophil purity was 92-96% and the viability of eosinophils was not less than 98%.

2) ANALYSIS OF INHIBITION OF CHEMOTAXIS.

In the Petri dish, with 24 cells, which served as the bottom of the camera, moved 600 ál LTB4(final concentration of 10-8M, Biochemical Cascade Ltd. (Cascade Biochemical co., Ltd.) in a solution of Hanks-Hepes-HSA, and then carried out the incubation at 37oC deoxycholate incubator for 30 minutes. After the upper chamber was connected to a Petri dish containing 24 cells, cellular chemotaxis, (polycarbonate membrane, pore size 3 μm, thickness 10 μm), which served as the upper chamber, separately added 200 μl (5106cells/ml) eosinophil suspension, pre-incubated at 37oC for 15 minutes in the chamber constant temperature. After two hours of reaction in deoxycholate incubator cell chemotaxis was removed; the logical saline solution. After cooling the mixture with ice using a counter formed elements of blood (trade name Coulter Counter) counted cells migrating to the lower liquid chamber. In the upper and lower chambers added the test drug dissolved in dimethylformamide to a final concentration of 10-5M

Equation 1.

The rate of inhibition of chemotaxis =

From table 2 it follows that the desired compound [I] of the present invention or its salt has a more potent inhibitory activity against eosinophilic chemotaxis than inhibiting activity of the compounds having a 7-position with triazolopyridazines patterns methyl group.

EXAMPLE 1 RETRIEVE.

(1) Connection example 3 - 10.0 mg

(2) Lactose - 60.0 mg

(3) Corn starch 35.0 mg

(4) Gelatin - 3.0 mg

(5) magnesium Stearate - 2.0 mg

A mixture of 10.0 mg of the compound obtained in example 3, 60 mg of lactose and 35.0 mg of corn starch was granulated through a sieve with openings of 1 mm, using 0.03 ml of a 10% aqueous solution of gelatin (containing 3.0 mg of gelatin), then it was dried at 40oC and again screened. The obtained granules were mixed with 2.0 mg of magnesium stearate and then under the spengiu sucrose, titanium dioxide, talc and gum Arabic. The coated tablets are polished with wax, this was the final coated tablets.

EXAMPLE 2 OBTAINING

(1) Connection example 3 - 10.0 mg

(2) Lactose 70 mg

(3) Corn starch 50 mg

(4) Soluble starch 7.0 mg

(5) magnesium Stearate - 3.0 mg

10.0 mg of the compound obtained in example 3 and 3.0 mg of magnesium stearate were mixed and granulated using 0.07 ml of an aqueous solution of soluble starch (containing 7.0 mg of soluble starch). The obtained granules were dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch, then realized the pressing and got the pills.

EXAMPLE 3 OBTAINING

(1) Connection example 3 - 5.0 mg

(2) sodium Chloride - 20.0 mg

(3) To obtain a total number equal to 2 ml, was added to distilled water. 5.0 mg of the compound obtained in example 3, and 20.0 mg of sodium chloride dissolved in distilled water and diluted with water to obtain a total number equal to 2 ml. of the resulting solution was filtered and aseptically placed in 2 ml ampoules, which were sterilized and sealed, receiving the injection.

INDUSTRIAL APPLICABILITY.

About the taxis, the compound [I] or its salt of the present invention is useful as a preventive/drugs against asthma, allergic rhinitis, atopic dermatitis, etc.

1. Triazolopyridine General formula I

< / BR>
where R1is a hydrogen atom or a lower alkyl group;

R2is2-6is an alkyl group or3-6-cycloalkyl group;

X is an oxygen atom;

Y is a group of the formula

< / BR>
where R3and R4is a hydrogen atom or a lower alkyl group;

R5and R6each independently means a hydrogen atom or a lower alkyl group;

m and n independently represent an integer from 0 to 4,

or its physiologically acceptable acid salt of the merger.

2. Connection on p. 1, where R2is a lower alkyl group having 2 to 6 carbon atoms.

3. Connection on p. 2, where the lower alkyl group is a branched C3-6is an alkyl group.

4. Connection on p. 1, where R1is a hydrogen atom; R2is2-6is an alkyl group; X is an oxygen atom; Y is a group of the formula

< / BR>
in which Rthe camping hydrogen or C1-6is an alkyl group;

m and n independently is 1 or 2.

5. Connection on p. 4, where R2is branched C3-6is an alkyl group.

6. Connection on p. 5, where R5and R6are a hydrogen atom, m and n are equal to 1.

7. Connection on p. 5, where C3-6is an alkyl group is an isopropyl group.

8. Connection on p. 1, selected from the group including

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-ethyl[1,2,4]-triazolo[1,5-a]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-n-propyl-[1,2,4] triazolo[1,5-a]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl-[1,2,4] triazolo[1,5-a]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl-[1,2,4] triazolo[1,5-a]pyridazin or its salt,

6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-tert-butyl-[1,2,4] triazolo[1,5-a]pyridazin or its salt,

6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-tert-butyl-[1,2,4] triazolo[1,5-a]pyridazin or its salt,

9. A method of obtaining a connection on p. 1, which includes the interaction of the compounds of formula

< / BR>
or its salt with the compound of the formula

< / BR>
or its salt, where Z1and Z2are tsepliaeva group, in response came the prevention or treatment of atopic dermatitis, characterized in that it contains from 0.01 to 100 wt.% connection on p. 1.

11. Pharmaceutical composition for inhibiting eosinophilic chemotaxis, characterized in that as the active ingredient contains an effective amount of the compounds on p. 1 together with a pharmaceutically acceptable carrier or diluent.

12. A method of treating atopic dermatitis in a mammal, characterized in that administered to a mammal an effective amount of the compounds on p. 1 together with a pharmaceutically acceptable carrier or diluent.

Priority points:

16.09.94 - PP. 1 - 7, 9 when R1is a hydrogen atom or a lower alkyl group; R2- C2-6is an alkyl group; X is an oxygen atom; Y is a group of the formula

< / BR>
where R3and R4is a hydrogen atom or a lower alkyl group; R5and R6each independently means a hydrogen atom or a lower alkyl group; m and n are independently an integer from 0 to 4;

22.09.94 - PP.1 - 7, 9 - when R2- C3-6-cycloalkyl group;

22.09.1994 - PP.8, 10 - 12.

 

Same patents:

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only their
The invention relates to organic chemistry, in particular to a method of obtaining 2', 3', 4',5'-tetrabenzyl-5-acetyl-1,5-dihydroquinoline (benzoflavone), and can be used in pharmaceutical industry and medicine
The invention relates to organic chemistry, particularly to a process for the preparation of secondary amines from the corresponding sulfonamides

The invention relates to a derivative pyrrolopyridine or their pharmaceutically acceptable salts, with high activity, inhibiting the secretion of gastric juice; activity, protects the mucous membrane of the stomach; and high antibacterial activity against Helicobacter pylori; and antiulcer agent containing the derivative or salt as an active ingredient

The invention relates to the derivatives of hintline formula (I), where n = 2 and each R2independently halogen; R3- (1-4C)alkoxy; R1di-[(1-4C)alkyl]amino(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)-alkoxy-(2-4C)alkyl] amino-(2-4C)alkoxy, and any R1containing methylene group, which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy, or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of inhibitory activity of compounds to inhibit the receptor tyrosinekinase in the treatment of proliferative diseases, such as cancer

The invention relates to substituted azetidinone General formula I listed in the description

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to inhibitors of glycogen phosphorylase, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia in mammals

The invention relates to derivatives of 3-acylamino-5-phenyl-1,4-benzodiazepine-2-it, and to their salts, retrieval method and intermediate products for their production

The invention relates to a derivative pyrrolopyridine or their pharmaceutically acceptable salts, with high activity, inhibiting the secretion of gastric juice; activity, protects the mucous membrane of the stomach; and high antibacterial activity against Helicobacter pylori; and antiulcer agent containing the derivative or salt as an active ingredient
Up!