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

 

(57) Abstract:

Usage: in the pharmaceutical industry. The essence of the invention: derivatives of 3(2H)pyridazinone f-crystals 1 or their pharmaceutically acceptable salts for certain values of the radicals and the pharmaceutical composition having protivotoksicheskoe, inotropic, vasodilator and antagonistic towards mediator activity, containing as active ingredient a compound of f-crystals 1 or its pharmaceutically acceptable salt in an amount of 0.5 to 95 wt.%. 2 S. p. f-crystals. Connection structure of f-crystals 1:

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10 Il., 12 table.

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient.

Description of the prior art:

1) In the field of substances possessing antithrombotic effect.

It is known that the aggregation of platelets plays an important role in the formation of solid radwaste who are thrombosis brain the lung thrombosis, myocardial infarction, occlusion of peripheral arteries, angina, etc., and to treat all these diseases it is necessary to develop new useful drugs. The attention of the General public attracted use as a preventive and therapeutic agent antithrombotic agent having inhibitory activity against the aggregation of platelets. It is still widely studied the effect of aspirin, not so long ago passed clinical trials ticlopidine and Cilostazol. However, there is a need for drugs with a stronger effect.

In addition to these various associated with thrombosis, diseases there are several diseases associated with platelets. Examples of such diseases are jade, metastasis cancer, etc. and have recently been conducted various studies, what preventive and therapeutic effects on these diseases mainly antithrombotic agents with the ability to control the function of platelets ("Journal of Poyal College of Physicians", v. 7, N 1, p. 5-18, 1972; "Japan clinics, hihon Rinsho)", v.4, N 6, R. 130-136, 1988; Anticancer Research, vol, 6,R. 543-548, 1986).

2) In the area of biological resources.

3) In the field of vasodilators

There are many vasodilators, but currently there are only a few drugs with favorable pharmacological characteristics of the circulatory system, in particular, a satisfactory inhibitory activity against the aggregation of platelets.

4) In the field means having resistance against SRS-A.

SRS-A (slow reacting substance allergies) is a chemical mediator released along with histamine, for example, the result of an allergic reaction and possess pharmacological activity in the sense of the ability to induce strong and long-lasting reduction of smooth muscles of the trachea. Their existence has long been known in this phenomenological aspect.

In 1979 it was found that the SRS-A is a mixture of leukotriene (hereinafter referred to as LTE4) [as a rule, is called a peptide leukotriene]

Conducted extensive research of SRS-A in the sense of its relationship with the painful condition. The result was a clear relationship SRS-A with allergic diseases of the immediate type, such as bronchial asthma, allergic rhinitis, urticaria and hay fever.

In addition, it has been suggested due SRS-A with various inflammatory diseases such as ischemic heart disease, etc.

Thus, it can be expected that the compounds having inhibitory activity against SRS-A, will be useful as a preventive or therapeutic drugs against disorders caused by or LTC4, LTD4or LTE4or mixtures thereof.

As antagonists of SRS-A was reported many used in medicine substances ("Drugs of the Future", v.12, R. 453-474, 1987); "Annual Reoports in Medical chemistry, vol. 22, R. 73-84, 1987, and "Annual Reviews in Pharmacological Toxicology", vol. 29, R. 123-143, 1989).

Not reported, however, no examples of their practical clinical applications.

The section describes the connection of 6-substituted, alkyloxy-3-(2H)-pyridazinone formula (1) and their pharmaceutically preumnozhena application Germany N 1 670 169), hereinafter called the source (a)) reveals 3(2R)-pyridazinone containing hydrogen or aliphatic, cycloaliphatic, arylaliphatic or aromatic group in 2-position, chlorine or bromine in the 4-position, alkylamino-group in 5-position and a chlorine atom or bromine, or hydroxy - or1-C4the alkoxy group in the 6-position.

Specified source (a) discloses a method for the synthesis of derivatives of 3(2H)-pyridazinone, their use as an intermediate in the synthesis of drugs or dyes, and is also used as intermediate products for the synthesis of various compounds. However, no mention of their pharmacological activity and is not given specific examples of such compounds. In addition, such compounds are not described specifically.

(b) has Not passed the examination of the patent application of Japan N 183675) 1983 (hereinafter referred to as the source (b)) reveals derivative 3(2H)-pyridazinone bearing a lower alkyl group at the 2-position, a hydrogen atom in the 4-position, a substituted or unsubstituted aniline group in position 5 and a hydroxyl group or a lower alkoxy group in 6-position.

Revealed that derivatives 3(2H)-pyridazinone have analgesic action, protivovospalitel the logical activity. (C) has Not passed the examination published patent application Japan N 30187/1988 posted for public review published application Europatent N 0275997 (hereinafter referred to as the source (in)) discloses derivatives of 6-substituted alkoxy-5-substituted, benzylamino-3(2H)-pyridazinones and their use as an agent with anti-SPS-A activity, which in some respects are similar to the compounds of the present invention.

As a result of extensive research it has been discovered that derivatives 3(2H)-pyridazinone and their pharmaceutically acceptable salts according to the invention, which differs from any of the compounds described in the following sources (a)-(C) represent a great connection in the sense of antithrombotic agents, cardiac stimulants, vasodilators, agents and/or anti-SRS-A agents, and that they can be included as active ingredients in the preventive or therapeutic medicines for the treatment of these different forms associated with thrombosis disease, heart failure, hypertension and/or asthma or allergic conditions of the immediate type. On the basis of this discovery was developed by the invention.

Thus their preparation and to pharmaceutical compositions containing them as active ingredient, and derived 3(2H)-pyridazinone is described by the following General formula (1)

Gde R1is a hydrogen atom, an alkyl group WITH1-C4with a straight or branched chain, Alchemilla group3-C4or group (CH2)nCO2R5/R5is an integer from 1 to 4, R5is a hydrogen atom or an alkyl group WITH1-C4with straight or branched purpose);

R2it AND1-Y1/A1this Allenova group1-C12with a straight or branched chain, Y1this CO2R5(R5as defined above), cyano group, CR6(R6is a hydrogen atom, an alkyl group WITH1-C4with a straight or branched chain or a phenyl group) or a group of teenie or pyridyl, which can be substituted in any position,

CON where R7and R8respectively and independently a hydrogen atom, an alkyl group WITH1-C4with a straight or branched chain, cycloalkyl group3-C8, phenyl group or the group thiazolyl or TeliaSonera, which can be substituted in any position, or R7and R8together form alkylnaphthalenes chain or a phenyl group or form morpholino ring with a nitrogen atom),

- SO2R9where R5defined above; R9is an alkyl group WITH1-C4with a linear or branched chain or a phenyl group which may be substituted by alkyl group WITH1-C4with a linear or branched chain, or a halogen atom),

where R10and R11respectively and independently a hydrogen atom, a halogen atom, an alkyl group WITH1-C4with a straight or branched chain, acylamino-group1-C4, OR5; R5defined above; NHSO2R9, R9as defined above, or a S/0 (m-R12, m is an integer from 0 to 2; R12an alkyl group WITH1-C4with a straight or branched chain), provided that R10and R11at the same time are not hydrogen atoms),

R14where R13a hydrogen atom, R14phenyl group, or R13and R14together form alkylenes group2-C8which may be substituted by alkyl group WITH1-C3with a straight chain,

CO2-R16where R15a hydrogen atom or an alkyl group WITH1-C4with a straight or branched chain; R16an alkyl group WITH1-C4with a straight or branched chain is mcilnay group1-C3with direct chain),

N where R17and R18respectively and independently an alkyl group WITH1-C4with a straight or branched chain, or R17and R18together form alkylenes group2-C8which may be substituted by alkyl group WITH1-C4with direct chain),

NN(CH2) where l is 1 or 2, k is an integer from 0 to 3; R19that is, an atom of hydrogen or halogen or

ONH or R2A2-Y2(A2Allenova group2-C10which may be substituted by alkyl group WITH1-C3with a straight chain, except when the carbon chain linking the oxygen atom with Y2contains one carbon atom, Y2phenyl group);

where R3and R4respectively and independently a hydrogen atom or a straight or branched alkyl group WITH1-C3;

X is a chlorine atom, a bromine atom, a hydrogen atom or cyano; and Ar is

where j is 0 or 1; R20a hydrogen atom, a halogen atom or or12where R12defined above,

(Z1this is an oxygen atom or a sulfur atom),

< / BR>
where R21a hydrogen atom or or5where R5defined above, or

where Z2and Z3-C4, OR22; R22a hydrogen atom or an alkyl group WITH1-C8with a straight or branched chain, or O-AND1-Y3AND1as defined above, Y3it is a phenyl group which may be substituted by straight or branched alkyl group WITH1-C4or a halogen atom, CO2R5or

CON where R5, R7and R8as defined above, or Z2and Z3together with the benzene ring form

where W forms alkylenes group1-C8which may be substituted by alkyl group WITH1-C3with a straight chain; and pharmaceutically acceptable salts thereof.

Values of R1, R2, R3, R4, X and Ar in the General formula I, which describes the connection of the invention will be explained below.

Examples R1include a hydrogen atom, methyl group, ethyl group, n-sawn group, ISO-sawn group, n-boutelou group, ISO-boutelou group, sec-boutelou group, tert-boutelou group, group: 2-propenyl, 2-methyl-2-propenyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropionyl, 4-methox propoxycarbonyl, ISO-propoxy - carbonylmethyl, 2-n-propoxycarbonyl, 2-ISO-propoxycarbonyl, 3-n-propoxycarbonyl, 3-ISO-propoxy - carbonitril, 4-n-propoxycarbonyl, 4-ISO-propoxycarbonyl, n-butoxycarbonylmethyl, ISO-butoxycarbonylmethyl, second-butoxycarbonylmethyl, tert - butoxycarbonylmethyl, 2-n-butoxycarbonylmethyl, 2-ISO-butoxycarbonylmethyl, 2-second-butoxycarbonylmethyl, 2-tert - butoxycarbonylmethyl, 3-n-butoxycarbonylmethyl, 3-ISO-butoxycarbonylmethyl, 3-second-butoxycarbonylmethyl, 3-tert-butoxycarbonylmethyl, 4-n-butoxycarbonylmethyl, 4-ISO-butoxycarbonylmethyl, 4-second-butoxycarbonylmethyl, 4-tert-butoxycarbonylmethyl, etc. is preferably a hydrogen atom, ethyl group and out-through the group, and more preferably a hydrogen atom.

Examples R2include1-Y1or A2-Y2where AND1Allenova group1-C12with a straight or branched chain, and2Allenova group2-C10which may be substituted by alkyl group WITH1-C3with a straight chain, except when the carbon chain between the oxygen atom with a group Y2contains one carbon atom.

Examples Y1 is butoxycarbonyl, ISO-butoxycarbonyl, second-butoxycarbonyl, tert-butoxycarbonyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, cyano group, hydroxyl, methoxy group, ethoxy group, n-propoxy group, ISO-propoxy group, n-butoxy-group, out-butoxy group, sec-butoxy group, tert-butoxy group, phenoxy group, carbarnoyl, N-methylaminomethyl, N-ethylaminoethanol, N-n-cuts - noncarbonyl, N-ISO-propylaminosulfonyl, N-n-butylaminoethyl, N-Deut-butylaminoethyl, N-ISO-butylaminoethyl, tert-butylaminoethyl, N-cyclopropanecarbonyl, N-cyclobutanecarbonyl, N-cyclopentanecarbonyl, N-cyclohexanecarbonyl, N-cycloheptylamine, N-cyclooctylmethyl, N-phenylenecarbonyl, N-2-thia - salaminioi, N-4-thiazolidinedione, N-5-thiazolidinedione, N-2-thiadiazolidine, N-5-thiadiazolidine, 1-aziridination, 1-azetidinone, 1-pyrrolidinecarbonyl, 1-piperidin - noncarbonyl, 1-homopiperazine, 1-(2,5-dimethyl)pyrrolidinecarbonyl, 1-(2,6-dimethyl)piperidinylcarbonyl, 1-(3-phenyl)-PI roleinfoarray, 1-(4-phenyl)piperidinylcarbonyl, N-methylsulfonylamino group, N-ethylsulfonyl group, N-n-propylsulfonyl, N-ISO-propylsulfonyl, N-n-butyl - phenylamino group, 1-morpholinoethyl, N-phenylcarbonylamino group, substituted on the nitrogen phenyl - sulfonylamino group (substituted stands, ethyl, n-propylene, ISO-propylene, n-butilkoi group, ISO-butilkoi group, sec-butilkoi group, tert-butilkoi group, fluorine atom, chlorine atom, bromine atom or iodine atom in the ortho -, meta - or para-position of benzene ring), substituted phenyl group (substituted methyl group, ethyl group, n-sawn group, ISO-sawn group, n-butilkoi group, ISO-butilkoi group, terbutaline group, tert-butilkoi group, fluorine atom, chlorine atom, bromine atom, iodine atom, formylamino group, acetylamino group, propionamido group, bucillamine group, methylsulfonylamino group, ethylsulfonyl group, N-n-propylsulfonyl group, N-ISO-propylsulfonyl group, N-n-butylsulfonyl group, N-ISO-butylsulfonyl group, N-Deut-butylsulfonyl group, N-tert-butylsulfonyl group, N-phenylcarbonylamino, hydroxy group, methoxy group, ethoxy group, a n-propoxy group, ISO-propoxy group, ISO-butoxy group, n-butoxy group, sec-butoxy group, a tert-butoxy group, substituted by Oh, ISO-sawn group, n-butilkoi group, ISO-butilkoi group, sec-butilkoi group, tert-butilkoi group, fluorine atom, chlorine atom, bromine atom or iodine atom in the ortho-, meta - or para-position of benzene ring), a methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio-group, out-butylthio group, sec-butylthio group, a tert-butylthio group, methylsulfoxide, ethylsulfate group, n-propylsulfonyl group, ISO-propyl - sulfoxy group, sec-butylsulfonyl group, n-butylsulfonyl-group, out-butylsulfonyl group, a tert-butylsulfonyl group, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, ISO-propylsulfonyl group, n-butylsulfonyl group, sec-butylsulfonyl group, ISO-butylsulfonyl group, sec-butylsulfonyl group, ISO-butylsulfonyl group, or tertbutylphenol group in ortho-, meta - or para-position of benzene ring), N-phenylcarbonylamino group, 1-(2-oxo) azetidine, 1-(2-oxo)-pyrrolidinyl, 1-(2-oxo-piperidinyl, 1-(2-oxo)homopiperazine, 1-(2-oxo-3,3-dimethyl)pyrrolidinyl, 1-(2-oxo-5,5-dimethyl)pyrrolidinyl, N-methoxy - carbylamine group, N-carbonylation group, N-ISO-butoxycarbonylamino group, N-Deut-butoxide-Beniamino group, N-tert-butoxycarbonylamino-group, 3-(2-oxo)-oxazolidinyl, 3-(2-oxo-5,5-dimethyl)oxazolidinyl, 3-2(2-oxo-4,4-diethyl)oxazolidinyl, 3-(2-oxo-5,5-diethyl)oxazolidinyl, N,N-disubstituted amino group (including an optional combination of a methyl group, ethyl group, n-sawn group, n-butilkoi group, terbutyl group and tert-butyl), 1-azetidine group, 1-pyrrolidino group, 1-piperidino group, 1-(2,5-dimethyl)pyrrolidino-, 1-(3,4-dimethyl)pyrrolidino-, 1-(4,4-dimethyl)piperidino-, 1-(4-phenylmethyl)piperazine-, 1-(4-diphenylmethyl)Pipa - Rodino group, 1-(4-substituted phenylmethyl)piperidinyl or 1-(4-disubstituted of phenylmethyl)piperazinyl (replaced by fluorine atom, chlorine atom, bromine atom or iodine atom in the ortho -, meta - or para-position of benzene ring), a group of phenylenecarbonyl, group N,N-duza - displaced of aminocarbonyl (including an optional combination of linear or cyclic alkyl groups, phenyl groups, thiazolyl or thiadiazolyl in the above-described N-substituted aminocarbonyl groups), N-alkyl-N-phenylcarbonylamino-, N-N-dialkyl - sulfonylamino - or N-alkyl-N-alkoxycarbonyl group (bearing linear or Rasul - phenylamino - or N-alkoxycarbonyl-group), disubstituted phenyl group (which is substituted in the ortho-, meta - or para-position of the benzene ring optional combination of a halogen atom, a linear alkyl group, acylamino group, hydroxy group, alkoxy group, N-phenylcarbonylamino group, N-alkylsulfonamides-group, the above substituted phenyl group), etc.

Examples Y2include phenyl group.

Examples R3and R4include a hydrogen atom, a methyl group, an ethyl group, a group, n-propyl group and ISO-propyl, preferably R3and R4represent a hydrogen atom.

Examples of X include a hydrogen atom, chlorine atom, bromine atom, cyano group, in the preferred embodiment, each Deputy is different from the hydrogen atom.

Examples of Ar include group 2-pyridyl, group 3-pyridyl, group 4-pyridyl, group substituted 2-pyridyl, 3-pyridyl or 4-pyridyl (replaced by fluorine atom, chlorine atom, bromine atom and iodine atom, methoxy group, ethoxy group, a n-propoxy group, ISO-Pro poxy group, n-butoxy-group, out-butoxy group, sec-butoxy group or tert-butoxy-group 2-, 3-, 4-, 5- or 6-position of the pyridine ring, a group of N-oxidability, relevant to the group 3-tanila, group, 1-naphthyl, 2-naphthyl, group, 1-naphthyl or 2-naphthyl (substituted hydroxy group, methoxy group, ethoxy group, a n-propoxy group, ISO-propoxy group, n-butoxy-group, out-butoxy group, sec-butoxy group or tert-butoxy group in an optional position of the naphthalene ring or a substituted phenyl group bearing one or two substituent in an optional combination in an optional position. Examples of the substituents include a hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, group, n-propyl group, ISO-propyl group, n-butyl group, ISO-butyl group, sec-butyl group, tert-butyl, hydroxy group, alkoxy group containing a linear or branched alkyl group WITH1-C8the group dioxymethylene, 1,2-dioxyethylene or 1,3-dioxypurine (which represents two adjacent substituent bonded together) or group 0-1-Y3. AND1represents a linear or branched alkylene group1-C10, Y3phenyl group, substituted phenyl group, [substituted methyl group, ethyl group, group, n-propyl group, ISO-propyl group, n-butyl group and ortho-, meta - or para-position of the benzene ring] or mentioned (in connection with the Y1group carboxyl, alkoxycarbonyl, 1-tsiklolineinye, 1-morpholinoethyl or carbamoyl, group N-substituted or N, N-disubstituted of aminocarbonyl bearing on the nitrogen atom by an optional combination of two substituents, which may be a hydrogen atom, a linear, branched or cyclic alkyl group, phenyl group, the group thiazolyl and group thiadiazolyl. Preferred examples include group 3-pyridyl or group type 3-substituted-4-methoxyphenyl, but we should not limit this invention to these examples.

In the above description, "h", "image", "second" and "third" substitute, respectively, "normal", "hard", "secondary" and "tertiary".

Preferred compounds among the compounds corresponding to General formula (I) of the invention are described following General formula IC,

where R1c is a hydrogen atom;

R2A1Y3', A1represents alkylenes group1-C12with a straight or branched chain; Y3' CO2R5, R5an alkyl group WITH1-C4with a straight or branched chain),

CON (R7and R8according to cloacina group3-C8or phenyl group, R7' and R8' together form alkylenes group2-C8which may be substituted by alkyl group WITH1-C3with a straight chain or a phenyl group, or form morpholino ring with a nitrogen atom),

- SO2R9(R5is a hydrogen atom or an alkyl group WITH1-C4with a straight or branched chain, R9' it's a phenyl group possibly substituted alkyl group WITH1-C4with a straight or branched chain or a halogen atom),

(R10' and R11' are independently and respectively a hydrogen atom, a halogen atom, an alkyl group WITH1-C4with a straight or branched chain, acylamino-group1-C4; OR5where (R5defined above); NHSO2R9"where (R9" an alkyl group WITH1-C4with a straight or branched chain) or S(0)m-R12where m is 0 or 2; R12an alkyl group WITH1-C4with straight or branched purpose, provided that R10' and R11' are not hydrogen atoms at the same time)

R14where R13'a hydrogen atom; R14phenyl group, or R13' and R14' together form Alki the group WITH1-C4with a straight or branched chain, R16'is an alkyl group WITH1-C4with a straight or branched chain, or R15' and R16' together form alkylenes group2-C6,

N where R17'and R18'respectively and independently, an alkyl group WITH1-C4with a straight or branched chain, or R17' and R18' together form alkylenes group2-C6,

NN(CH2) where l is 1 or 2; R19is a hydrogen atom or halogen atom)

or

ONH or R2it AND2Y2where AND2Allenova group2-C8which may be substituted by alkyl group WITH1-C3with a straight chain, except when the carbon chain between the oxygen atom with a group Y2contains one carbon atom, and Y2this phenyl group);

XC' is a chlorine atom, a bromine atom, or cyano group; and

And' this is group 3-pyridyl or

OMe where Z3halogen atom, an alkyl group WITH1-C4with a straight or branched chain, OR22where R22is a hydrogen atom or an alkyl group WITH1-C8with a straight or branched chain) or O-AND3-Y3where AND3alkylene and R8' is defined above.

Compounds of General formula I according to the invention include optical isomers and stereoisomers based on 1-6 asymmetric carbon atoms.

In table. 1 are typical representatives of compounds derived derived 3(2H)-pyridazinone General formula I and their pharmaceutically acceptable salts according to the invention, but should not limit the invention provides compounds.

Table 1: "n" means normal, "i" means ISO "sec" means secondary, "Me" denotes a methyl group, "Et" means ethyl group, "Pr" represents a propyl group, "Bu" represents a butyl group, "Pen" refers to the group pentile, "Hex" refers to a group of exile, "Hep" means a heptyl group, "Oct" refers to a group Attila, "AC" means acetyl group, and "Ph" denotes a phenyl group.

Q1-Q108 in table. 1 is a group corresponding to formula shown in Fig. 1-10.

Next explained is a method of obtaining compounds according to the invention.

Derivative 3(2H)-pyridazinone General formula (1) and their pharmaceutically acceptable salts according to the invention can be obtained in the following ways in accordance with the scheme is that bromine; X2a chlorine atom, a bromine atom or a hydrogen atom; R1, R2, R3, R4and Ar is defined above.

Method for producing corresponding to the reaction scheme (I), the compound of formula (11A) 4,5-dihalogen - or 5-halogen-3(2H)pyridazinone interacts with derivative arylmethylidene formula (III) or its salt in the presence of dehydrohalogenating agent, optionally in an inert solvent, with the formation of the compounds of formula (IA), in which the structure of the carbon atom at the 4-position of the compounds of formula (I) according to this invention is associated with X2.

a chlorine atom or a bromine atom, is formed as a by-product of the positional isomer of compounds of formula (IA), i.e. a compound of formula (VA)

VA where R1, R2, R3, R4X1and Ar is defined above containing substituted in 4-position of arylmethylidene group, but the ratio in which the formed compounds of formulas (IA) and (VA), depends primarily on the polarity of the solvent used.

Namely, when using a highly polar solvent has a tendency to high value of the ratio of the performance of the compound (IA) according to the invention. On the contrary, in cases where ispolzuetsa relations performance of the compound (VA).

Therefore, as solvents, providing suppression of education as a by-product of the compounds of formula (VA) and efficient production of compounds (IA) according to the invention can be mentioned solvents such as ether, such as tetrahydrofuran or 1,4-dioxane, amide type solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-organic, acetonitrile, dimethylsulfoxide, alcohol solvents such as methanol, ethanol or propanol, organic amines such as pyridine, triethylamine, N,N-dimethylaminoethanol or triethanolamine, water or mixtures of these substances.

The desired compounds of formula (IA) according to this connection can be easily isolated from a mixture of compounds of formulas (IA) and (VA) and cleaned using conventional methods known per Sl in organic synthesis, such as fractional recrystallization or various types of chromatography on silica gel.

In the case of the compounds of formula (IIA), in which X2is a hydrogen atom, such as 5-halogen-3(2H)-pyridazinone, as solvents in the reaction can be used, in addition to the above solvents, and benzene, toluene, xylene, n-hexane, n-GE is romily hydrogen. As a rule, it is possible to increase the output by introducing into the reaction system dehydrohalogenating agent linking this halogenation.

You can use any dehydrohalogenating agent, does not affect adversely on the reaction and is capable of capturing hydrogen halide. As such dehydrohalogenating agents may be mentioned inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, or organic bases, such as N,N-dimethylaniline, N, N-diethylaniline, trimethylamine, triethylamine, N,N-dimethylaminoethanol or pyridine.

On the other hand, as dehydrohalogenating agent you can use the original arylmethylidene-derivative of formula (III) taken in excess. In many cases this provides increased output.

The reaction temperature can range from 10aboutC to the boiling point of the solvent used for the reaction.

The molar ratio between the starting substances can be set arbitrarily. However, arylmethylidene - derivative of formula (III) or its salt can usually be used in amounts of 1 to 10 moles, predpochtite halogen - or 5-halogen-derivative 3(2H)-pyridazinone formula (IIA) can be obtained through the traditional method or by conventional reactions of organic synthesis, as is described below.

Namely, 4,5-dihalogen - or 5-halogen-derived 3-(2H)-pyridazinone formula (IIa) can be obtained according to the method, opened in the above-mentioned source ().

Those of arylmethylidene derivatives of the formula (III) and their salts in method (I), which do not accrue to the market as industrial products, can be obtained according to the method disclosed in not the examined published patent application Japan N 267560/1986. The reaction scheme (2):

where R1, R2, R3, R4X1and Ar is defined above.

The scheme of the reaction (2) illustrates the method of obtaining 4-cyano-5-arylmethylidene-derivative of formula (IB) of this invention by substitution reactions of halogen between 4-halogen-5-arylmethylidene-derivative of the formula (IB-a) and lanita metal of the formula (IV).

Examples of the metal M include lithium atom, a sodium atom, a potassium atom, a copper atom, etc.

As the reaction solvent are preferably used solvents, amide type, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-organic and other alcohol solvents such as methanol, ethanol, n-propanol, n-butanol, etc. sulfoxide and aqueous solvents.

Tempo is atory to the boiling point of the solvent, used for the reaction. Typically, the reaction involving compounds, the halogen atom in the 4-position of the formula which represents bromine, proceeds under milder temperature conditions compared with the reaction involving chlorine atom.

The molar ratio between the starting substances can be defined arbitrarily, and it is sufficient that the metal cyanide of the formula (IV) is used in an amount of 1.2 to 10 moles to one mole of the 4-halogen-5-arylmethylidene-derivative of the formula (IB-a).

The desired compound can be easily isolated and cleaned known in organic synthesis method, for example, recrystallization, chromatography on silica gel different types or distillation.

The reaction scheme (3)

< / BR>
< / BR>
where R1' an alkyl group WITH1-C4with a linear or branched chain, Alchemilla group3-C4or (CH2)nCO2R5this chlorine atom, bromine atom, iodine atom or other aluminium functional group; h, R2, R3, R4, R5, X and Ar are defined above.

The above reaction scheme (3) illustrates a method of obtaining a product substitution in 2-position of the formula (1-b) according to the invention in the ot is asevidence compounds of formula (I) of the invention, with a reactive derivative containing aliminium group, such as halogen derivatives, alkylsulfonate derived or vinylsulfonate derivative corresponding to the formula R1' hal.

This reaction is in General carried out in the presence of inorganic bases such as potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, etc. or in the presence of organic bases such as triethylamine, tri-n-Propylamine, etc.

In the case when R3in the compound of the formula (I-a) represents an alkyl, can be used, in addition to the above inorganic bases, metal hydrides and ORGANOMETALLIC compounds such as sodium hydride, n-utility etc.

As the reaction solvent can be used, in the case of the application of inorganic or organic bases, solvent type, ketones (acetone, methyl ethyl ketone, diethylketone and others), an amide type solvent (formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and others), alcohol solvent (methanol, ethanol and others), water and mixtures thereof, and in the case of metal hydride solvent of the ether type.

aboutC to the boiling point of the solvent, and the use of metal hydride she usually ranges from -78 to 60aboutC.

The molar ratio between the starting materials can be defined arbitrarily. But enough of the reactive derivative of formula R1hal was used in an amount of from 1 to 5 moles per one mole of the compounds of formula (I-a)

The desired compound can be extracted and cleaned according to the method, the description of which is cited in connection with reaction scheme (2).

The reaction scheme (4)

< / BR>
where R1, R2, R3, R4, X, Ar and hal are defined above.

The above reaction scheme (4) illustrates the method of obtaining the compounds of formula (I) according to the invention by reacting 6-hydroxy-5-arylmethylidene-derivative of the formula (10-a) with a reactive derivative of formula R2-hal. 6-Hydroxy-5-arylmethyl-derivative of the formula (10-a) used in this reaction as the starting material can be obtained by methods disclosed in the above-mentioned source (in) and the reaction scheme (2).

As regards the reaction conditions, it should be conducted under conditions similar to those used when carrying out the reaction according prevedeno the first metal, R1" protective group, and R1, R2, R3, R4, X and Ar are as defined above).

The above reaction scheme (5) illustrates a method of obtaining a 6-alkoxy-5-arylmethylidene-derivative of formula (I) or formula (I-a) of the invention by substitution reaction of the nitro-group 6-nitro-5-arylmethylidene-derivative of formula (ID-a) or (ID-b) with an alkali metal alkoxide of the formula (VI). Used as starting material for the reaction of 6-nitro-derivative of formula (ID-a) and (ID-b) can be obtained in accordance with the method described in the above-mentioned source ().

Connection with a hydrogen atom in the 2-position of pyridazinone, which is one of the desired compounds can be obtained by direct, as shown in the reaction scheme (5)-(i) where R1in the formula (1D-a) and (I) represents hydrogen, or path, shown in the reaction scheme (5)-(ii), which represents the conversion of 6-nitro-5-arylmethylidene-derivative of formula (ID-b), protected at the 2-position by a group R1"in the compound of formula (ID-c), with the subsequent removal of the protective group R1"the aim of which is to obtain the desired compound. In many cases, the output is typically better upon receipt by the latter method.

As dilatometer (Me3SiCH2CH2OCH2-), pivaloyloxymethyl (Me3C-CO2CH2- , gasoline - oximeter ( CH2OCH2-), hydroxymethyl, methoxymethyl (MeOCH2- or CO2R, where R is lower alkyl.

The removal of the protective group R1" you can easily make an ordinary method used for the removal of such protective groups.

Here alkali metal in the formula M1represents lithium, sodium or potassium.

Therefore, the alkoxides of the alkali metal in the formula (VI) used as the nucleophilic agent, include alkoxides of metals, which correspond to the above definition of M1and R2.

Relative to the solvent of the reaction there are no particular restrictions as long as the solvent is inert to the reaction, and can provide a list of the amide type solvents such as N-organic, formamide, N, N-dimethylformamide or N, N-dimethylacetamide), solvent-type ethers (such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane), solvents like benzene (such as benzene, toluene or xylene), as well as mixtures of these substances.

The reaction temperature varies depending on the use of a reaction solvent.

The molar ratio between the starting materials can be defined arbitrarily, and it is sufficient that the alkali metal alkoxide of the formula (VI) was used in an amount of from 1.2 to 10 moles to one mole of 6-nitro-5-arylmethylidene-derivative of formula (ID-a) or (1D-b).

The desired compound can be easily isolated and cleaned known in organic synthesis method, for example, recrystallization, chromatography on silicagel different types or distillation.

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where R1, R2, R3, R4X1and Ar is defined above.

The above reaction scheme (6) illustrates the method of obtaining the compounds of formula (IE) according to the invention, in which the structure of the 4-position is occupied by a hydrogen atom by reductive removal of the halogen atom at the 4-halogen derivative of the formula (IB-a).

As the restore method is usually used for catalytic hydrogenation. As catalysts it is possible to enumerate palladium, platinum oxide, Nickel catalyst of Raney, etc., and the reaction proceeds relatively smoothly when the hydrogen pressure from 1 to 10 ATM.

In those cases where R2contains the atom, which poisons the catalyst, the preferred result.

As the solvent the reaction using the liquid solvent in the case of the reaction of catalytic hydrogenation, and the use of metal hydride is used, as a rule, the solvent type simple ether.

The reaction temperature may range usually from -10 to 100aboutC, and the reaction usually proceeds smoothly.

The reaction scheme (7)

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where R1, R3, R4, R5, R7, R8, A1, X and Ar are defined above.

The above reaction scheme (7) illustrates the method of obtaining 6-aminocarbonylmethyl-derivative of formula (IF-b) by carrying out the condensation reaction, including dehydration, a 6-carboxyaniline-derived or 6-alkoxycarbonylmethyl-derivative of formula (IF-a) and the amine of formula (VII).

In the case when R5represents a hydrogen atom, the condensation process can be performed according to the method known from the synthesis of peptides, for example, chloranhydride way, mixed chloranhydride method or by a method involving the use of a condensing agent, such as dicyclohexylcarbodiimide, carbonyldiimidazole or imide, N-hydroxy-succinic acid, and condensation method chosen is such reaction conditions.

In the case of reaction with vysokoselektivnymi amines which correspond to the formula (VII), condensation may occur even when using esters, in the formula which R5 represents an alkyl group. In this case, the type of solvent is not limited specifically, and can be used any solvent, if it does not affect adversely on the reaction. In some cases, the reaction may proceed in the absence of solvent. The reaction temperature ranges from room temperature up to 200aboutC, more usually from 50 to 150aboutC. the reaction Scheme (8)

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where R1, R2, R3, R4, R5, R7, R8,X, Z2and AI is defined above.

Carried out the reaction scheme (8) illustrates the method of obtaining amido-derivative of formula (IG-b) by the condensation reaction between 5 - (carboxyaniline)phenylethylamine - or 5 - (alkoxycarbonylmethyl)phenylethylamine-derivative of formula (IG-a) and the amine of formula (VII).

This reaction can be performed exactly the same as the reaction scheme (7).

The reaction scheme (9)

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where R1, R2,R3, R4, R20and X is defined above.

The above reaction scheme (9) illustrates the ring 5 pyridylmethylamine-derived formula (IR-a). Examples of oxidants include naturalyou acid, peracetic acid, adventurou acid, metaglidasen acid, tert-butylhydroperoxide, aqueous hydrogen peroxide, etc.

As reaction solvents include halogen solvents (carbon tetrachloride, chloroform, diplomaten, 1,2-dihloretan and others ), solvent type, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane and other), solvents like benzene (benzene, toluene, and others), solvents such as alcohols (methanol, ethanol, tert-butanol, and others), acetic acid, formic acid, etc. In some cases added as a catalyst complex of the transition metal.

The reaction temperature usually ranges from -20aboutC to the boiling point of the used solvent.

The molar ratio between the starting materials can be set arbitrarily, but the oxidizing agent is used usually in an amount of from 1 to 10 mol, preferably from 1.2 to 5 moles, to one mole of the 5 pyridylmethylamine-derived formula (IR-a).

The desired compound can be easily isolated and cleaned known in organic synthesis methods, for example by recrystallization, chronorally (I) or their pharmaceutically acceptable salts according to the invention can be mentioned non-oral use in the form of injection (subcutaneous, intravenous, intramuscular or intraperitoneal), ointments, suppositories or aerosols and oral use in the form of tablets, capsules, granules, pills, syrups, liquids, emulsions or suspensions.

Mentioned pharmaceutical composition comprises the compound according to the invention in amounts of about 0.1 to 99.5 wt. preferably approximately from 0.5 to 99.5 wt. calculated on the total weight of the composition.

The connection according to the invention or the compositions containing the compound according to the invention may be added other pharmacologically active compounds.

In addition, the composition according to the invention can contain a variety of compounds according to the invention.

Clinical dose of the compounds according to the invention varies depending on age, body weight, sensitivity or observed in patient symptoms, etc. Usually, however, the effective daily dose of 0.003 to 1.5 g, preferably 0.01 to 0.6 g for an adult patient.

If necessary, however, you can use the dose is outside the specified range.

Depending on the method of use, the compounds according to the invention can be introduced in various suitable compositions in accordance with the ordinary is pills, capsules, granules or pills for oral use, using such excipients as sugar, lactose, glucose, starch or mannitol; a binder such as syrup, gum Arabic, gelatin, sorbitol, tragakant, methylcellulose or polyvinylpyrrolidone; disintegrant, such as starch, carboxymethyl cellulose or its calcium salt, powder, crystalline cellulose, or polyethylene glycol; imparting lubricity agents, such as talc, magnesium stearate or calcium or silica; or a lubricant such as sodium laurate or glycerin.

Solutions for injection, solutions, emulsions, suspensions, syrups or aerosols can be prepared by dissolving the active ingredient in a solvent, for example water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol, or polyethylene glycol; introducing a surface-active additive, for example, ether of sorbitol and fatty acid ester of polyoxyethylene, sorbitan and fatty acid ester of polyoxyethylene, sorbitan and fatty acid ester of polyoxyethylene and fatty acids, polyoxyethylene ether of hydrogenated castor oil or lecithin, suspensorium additive, such as sodium carboxymethyl cellulose, a derivative of cellulose, this to the R peroxybenzoyl acid, benzylaniline or salt of sorbic acid.

Similarly it is possible to make suppositories using, for example, polyethylene glycol, lanon or coconut oil.

The best way to implement the invention (examples getting, examples, formulas, and sample tests).

The following is a detailed description of the invention with reference to examples, including sample receipt, sample formulas and sample tests. It should however be understood that the invention is in no way limited to these specific examples. In the description of examples of the preparation, as well as in table.2, symbols "NMP", "IR" and "MS" means "spectrum of nuclear magnetic resonance, infra-red spectrum" and "mass spectrometry", respectively. IR spectra were shot by the method of the disk of bromide of potassium, and NMR in chloroform containing heavy hydrogen, except where otherwise indicated.

In the data of mass spectrometry in the table.2 shows only the main peaks, or the typical peaks of the fragments.

Example of getting 1. 4-Chloro-5-(3,4-dimethoxyphenethylamine)-6-(5-ethoxycarbonylmethoxy)-3(2H)-PI ridazine (compound I).

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A mixture of 4.13 g of 4,5-dichloro-6-(5-ethoxycarbonylmethoxy)-3(2H)-PI ridazine under stirring. Boiled away the solvent under reduced pressure, the residue poured water, whereupon the product was extracted with chloroform. The extract was washed with diluted hydrochloric acid, water and a salt solution in the order listed and dried over sodium sulfate. Then drove the solvent and has led the residue from a mixture of chloroform(n-hexane)diethyl ether, resulting in the above compound in the form of colorless crystals with a melting point of from 111 to 112aboutC.

NMR: 11,71 (1H, broad singlet), of 6.71 (3H, singlet), 5,02 (1H, compressed triplet), was 4.76 (2H, doublet), 4,11 (2H, triplet), 3,80 (6N, singlet), of 3.57 (3H, singlet), and 2.26 (2H, triplet), 2,1-1,2 (6N, multiplet).

MS (m/e): 439 (M+), 404, 151 (100%).

Example of getting a 2. 4-Chloro-5-(3,4-dimethoxyphenethylamine)-6-(5-carboxypentyl)-3(2H)-pyridazin - non(compound 2).

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A mixture of 240 mg of 4-chloro-5-(3,4-dimethoxyphenethylamine)-6-(5-ethoxycarbonylmethoxy)-3(2H)-PI reed(compound (I) obtained according to the method of example obtaining 1, 65 mg of sodium hydroxide, 10 ml of methanol and 1 ml water was stirred at 60 70aboutC for 1 h After the reaction mother liquor is boiled away under reduced pressure, the residue poured water and brought the pH of receiving what orapharma. Washed extract water and salt solution in the order listed and dried over sodium sulfate. Then drove the solvent and has led the residue from a mixture of chloroform (diethyl ether, which gave 192 mg of the above compound in the form of colourless crystals with a melting point 150,5-151,5aboutC.

NMR 6,70 (3H, singlet), 5,14 (1H, compressed triplet), and 4.75 (2H, doublet), 4,10 (2H, triplet), 3,79 ( 6N, singlet), to 2.29 (2H, triplet), a 2.0-1,2 (6N, multiplet).

IR: (maxKBrcm-1): 3100, 2910, 1720, 1610.

MS (m/e): 425 (M+), 390, 151 (100%).

Example of getting a 3. 4-Bromo-5-(3-pyridylmethylamine)-6-(3-phenylpropoxy)-3(2H)-pyridazinone hydrochloride (compound N 85)

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Dissolved 2.50 g of 4-bromo-(3-pyridylmethylamine)-6-(3-phenylpropoxy)-3(2H)-PI - redazione (compound 101) in 150 ml of 10% aqueous solution of hydrogen chloride in methanol and the resulting solution was stirred at room temperature for 1 h boiled away the solvent under reduced pressure, and has led the residue from methanol/diethyl ether gave of 2.68 g of the above compound in the form of colourless crystals with a melting point of 203 to 205aboutC.

MS (m/e): 414 (M+-HCl), 335, 322, 296, 217, 118 (100%).

Example 4. 4-Chloro-5-(3,4-is telchargement added to the mixture, consisting of 200 mg of 4-chloro-5-(3,4-dimethoxyphenethylamine)-6-(5-carboxypentyl - Loxy)-3(2H)-pyridazinone (compound 2), obtained by the method of example getting 2, 60 mg of triethylamine and 10 ml of tetrahydrofuran, and the mixture was cooled with ice and stirred the mixture at the same temperature for 1.5 hours Next to it was added 100 mg of diethylamine and the resulting mixture was further stirred for 2.5 h, after removing the ice bath, and then boiled away the solvent under reduced pressure. To the residue was added water and the product was extracted with chloroform. The extract was washed with brine and dried over sodium sulfate. Then the solvent was removed by distillation and has led the residue from a mixture of chloroform/diethyl ether, resulting in 209 mg of the above compound in the form of colorless crystals with a melting point of from 148 to 149.5aboutC.

NMR, of 6.75 (3H, singlet), of 5.15 (1H, compressed triplet), 4,79 (2H, doublet), is 4.15 (2H, triplet), 3,83 (6N, singlet), 3,81, 3,76 (each 2H, Quartet), and 2.27 (2H, triplet), 2,1-1,9 (6N, multiplet), 1,15, 1,10 (each 3H, triplet).

MS(m/e): 480 (M+), 445, 310, 275, 170 (100%), 151.

Example of getting a 5. 4-Chloro-5-(3,4-dimethoxyphenethylamine)- -(5-N-methylaminoacenaphthylene)-3(2H)-(compound 8)

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The mixture, consisting is obtained by the method of example obtaining 1.2 ml of 40% aqueous solution of methylamine and 6 ml of methanol, was heated under reflux for 8 hours boiled away the reaction mixture under reduced pressure and the product was extracted with chloroform. The extract was washed in turn with water and brine, and then dried over sodium sulfate. Then drove the solvent and has led the residue from a mixture of chloroform/diethyl ether, so what happened 146 mg of the above compound in the form of colorless crystals with a melting point 103-104aboutC.

NMR of 11.75 (1H, broad singlet), was 6.73 (3H, singlet), from 6.0 to 5.5 1H, broad multiplet), 5,02 (1H, compressed triplet), was 4.76 (2H, doublet), 4,10 (2H, triplet), 3,81 (6N, singlet) 2,74 (8H, doublet), 2,12 (2H, compressed triplet), 1,9-1,3 (6N, multiplet).

MS (m/e): 438 (M+), 403, 310, 274, 151 (100%), 128.

Example of getting a 6.

4-Chloro-5-(3-pyridylmethylamine)-6-[5- (1-piperidinecarbonitrile)]-3(2H)- pyridazinone fumarate (compound 73)

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A mixture consisting of 1.0 g of 4-chloro-5-(3-pyridylmethylamine-6-[5-(1-piperidinecarbonitrile)]-3(2H)-b IRIG(compound 33), 268 g of fumaric acid and 20 ml of methanol was stirred at room temperature for 1 h boiled away the reaction mixture under reduced pressure and recrystallize the solid residue from a mixture of chloroform/ethyl acetate, getting in Rees.

MC(m/e): 433 (M+-(CH-CO2H2)2), 398, 287, 251, 216, 182 (100%).

Example of getting a 7.

4-Cyano-5-(3-pyridylmethylamine)-6-[3- (4-chlorpheniramine)]-3(2H)-pyridazin-he (compound 107).

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A mixture consisting of 1.0 g of 4-bromo-5-(3-pyridylmethylamine)-6-[3-(4-chlorphenyl - poxy)]-3-(2H)-pyridazinone (compound 106), 587 mg of copper cyanide and 20 ml of N-methylpyrrolidone, was stirred for 6 hours at 120-130aboutC. After cooling the mixture to room temperature, thereto was added a saturated aqueous solution of ammonium chloride, after which the product was extracted with chloroform. The extract was washed with saline and dried over sodium sulfate. Then the solvent was distilled and has led the residue from acetonitrile, getting 313 mg of the above compound in the form of slightly yellowish crystals with a melting point of 188 to 190aboutC.

MS (m/e): 395 (M+), 350, 243, 152 (100%), 124.

IR:(maxKBrcm-1): 3100, 2850, 2200, 1620.

Example of getting 8. 2-Ethoxycarbonylmethyl-4-bromo-5-(3,4-dimethoxyphenethylamine)-6-[3-(4-Harbin - silverprotec)]-3(2H)-pyridazinone (compound 238).

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A mixture consisting of 100 mg of 4-bromo-5-(3,4-dimethoxyphenethylamine)-6 -[3-(4-chlorophenyltrichlorosilane, was stirred at reflux for 5 hours After nerastvorim material was removed by filtration,boiled away the solvent under reduced pressure and to the residue was added water, whereupon the product was extracted with chloroform. The extract was washed with saline and dried over sodium sulfate. Then drove the solvent, and the residue was subjected to purification by way of column chromatography on silica gel (eluant: n-hexane)in ethyl acetate -1(1), which gave 82 mg of the above compound as a colourless oil.

MS (m e): 593 (M+), 514, 288, 259, 151 (100%).

Example of getting a 9. 2-(Carboxymethyl)-4-bromo-5-(3,4 - dimethoxyphenethylamine)-6-[3-(4-chlorpheniramine)] -(2H)-pyridazinone (compound 227).

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A mixture consisting of 80 mg of 2-ethoxycarbonylmethyl-4-bromo-5(3,4 - dimethoxyphenethylamine)-6-[3-(4-chlorpheniramine)] 3(2H)-pyridazinone (compound 238) obtained by the method of example obtaining 8, 16 mg of sodium hydroxide, 2 ml of methanol and 0.2 ml of water was stirred at room temperature for 2 hours After the reaction mother liquor is boiled away under reduced pressure, the residue poured water and brought the pH of the resulting solution to 1-2 with dilute hydrochloric acid, after h is Then the solvent was distilled, and the residue was led from a mixture of chloroform (diethyl ether, receiving 49 mg of the above compound in the form of colorless crystals with a melting point 140-141aboutC.

MS (m/e): 486 (M+-Br), 427, 371, 151 (100%).

Example 10. 4-Bromo-5-[3-(N-oxopyrimidine)] -6-(3-phenylpropoxy)-3(2H)pyridazinone (compound 230).

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A mixture consisting of 250 mg of 4-bromo-5-(3-pyridylmethylamine)-6-(tinyproxy)-3(2H)-pyridazinone, 167 mg of meta-chlorbenzoyl acid and 10 ml of dichloromethane, was stirred at room temperature for 6 hours To the mixture was added saturated aqueous sodium hydrogen carbonate solution and chloroform, and then separated the organic layer. The remaining aqueous layer was extragonadal chloroform and joined the extract obtained with the first organic layer. The combined extract was washed with water and brine in turn and dried over sodium sulfate. Then drove the solvent, and the obtained solid residue was recrystallize from a mixture of chloroform/diethyl ether, which gave the above compound in the form of colorless crystals with a melting point 191-192aboutC, MS (m/e): 414 (M+With), 335, 323, 295, 217, 91 (100%).

Compounds described in needleworking numbers of the compounds in the table.1. The rightmost column in the table.2 indicates the number of sample receipt, whereby was obtained a connection.

An example of a formula 1 (tablets) Connection N 85 10 g Lactose 20 g Starch, 4 g Starch for paste 1 g magnesium Stearate 0.1 g of Calcium carboxymethyl cellulose 7 g Total 42,1 g

These components are mixed in the usual way, and formulated in the form of a coated sugar tablets, each containing 50 mg of active ingredient.

Example formula 2 (capsule) Compound N 88 10 g Lactose 20 g of Microcrystalline cellulose 10 g magnesium Stearate 1 g 41 g

These components were mixed in the usual way and the mixture was filled gelatin capsules, so what happened capsules, each containing 50 mg of active ingredient.

An example of a formula 3 (soft capsules) Connection 94 10 g Corn oil 35 g Only 45 grams

These components were mixed and formulated in the usual way, so as to obtain soft capsules.

Example formula 4 (ointment) Connection N 55 1.0 g Olive oil 20 g White petrolatum 79 g Total 100 g

The above components were mixed in the usual way, to get 1% ointment.

Example formula 5 (aerosol Santa - floridana 73,25%

Mixed specified composition (A). Thus obtained dissolved, the mixture was loaded into a container fitted with a valve, and propellant (B) was applied from a nozzle valve until the gauge pressure of approximately from 2.46 to 2,81 mg/cm2so as to gain an aerosol suspension.

Test method

1. The effect of suppressing adhesion of platelets

1). Test in vitro

(A). The effect of suppressing adhesion of platelets in rats.

Collected blood from the Central artery of male white Japanese rats (weight 1.8-2.5 kg) in the pipette, 1/10 volume of which was occupied by 3.8% sodium citrate.

Thus obtained blood was subjected to centrifugation at 200g for 7 min at room temperature, which was aimed at obtaining platelet-rich plasma (OTP). The residue was further subjected to centrifugation at 2000q for 10 minutes to obtain platelet-poor plasma (BTP). The measurements were carried out on diluted to 300 000/mm3BTP and OTP. Plasma CRP and BTP were placed in a cuvette and set the transmission interval to 0% in the case of OTP and 100% for BTP. Then to OTP added a sample of the test drug dissolved in 100% dimethyl sulfoxide (DMSO): final concentration of DMSO of 0.25% After a thermos is th clumping. Called the test sample medication effect of suppressing adhesion of platelets was evaluated as the concentration (IC50M), where aggregation control sample was reduced to 50% of the Agents contributing to the aggregation of ADP and arachidonic acid (A.) was administered at the minimum concentration (ADP: 5-10 M; A. A. 0.2-0.3 mm), causing the most intense aggregation. Measurement of the degree of aggregation was performed using NBS DUMB TRACER 601.

(B) the Effect of suppressing the aggregation of platelets in Guinea pigs

Collected blood from the Central artery of male Guinea pigs of the Hartley type (weighing about 300 g) similarly, as described above, and subjected to centrifugation at 160g for 10 min at room temperature in order to obtain the OTP. The residue was further subjected to centrifugation at 3000g for 10 minutes OTP for measurement was prepared in the same manner as in the above experiment on rats, and added, to calculate the concentration values IC50by which the sample is observed 50% inhibition of aggregation of platelets, sample test drug dissolved in 100% DMSO (final concentration of DMSO: 0,5). As the agent that causes the aggregation of trombone clumping of platelets in rats.

After the male Japanese white rabbits (weight: 1.8 to 2.5 kg) were fasted for 18 h, he introduced the oral sample tested drugs in the form of a suspension in 0.5% methylcellulose. After drug administration from the ear artery were periodically collected blood, and to assess the adhesion of platelets caused by each aggregating agent, prepared OTP exactly the same as in the above test in vitro. The effect caused by the test drug was evaluated by the ratio of suppressed aggregation, which is calculated under the assumption that before drug administration aggregation of platelets was 100%

(B) the Effect of suppressing adhesion of platelets in Guinea pigs

(1) After the male Guinea pigs of the Hartley type (weight: about 350 g) were starved for 18 h, he oral introduced sample tested drugs in the form of a suspension in 5% solution of gum Arabic. After the introduction of drugs from the Central artery periodically, the blood was collected and prepared the OTP, as in the above test in vitro, to measure the aggregation of platelets caused by each aggregating agent. The effect of the test drugs were evaluated for suppression of aggregation, which was calculated in soldiers Hartley (weight: about 350 g) were starved for 18 h, him oral introduced sample tested drugs in the form of a suspension in 5% solution of gum Arabic. One hour after the introduction of the collected blood from the Central artery and prepared the OTP in the same way as in the above test in vitro, with the aim of measuring the aggregation of platelets induced by each of the aggregating agents. The effect resulting from the introduction of the sample of the tested drugs was assessed by the ratio of depressed aggregate, calculated on the assumption that before drug administration aggregation of platelets was 100%

(C) Simulation of thrombocytopenia in mice

Collagen (Hormon-Chemie Co. Ltd.), diluted in isotonic sodium chloride was administered to male ICR mouse (weight 24-30 g) through the tail vein in an amount of 1 mg/5 ml/kg Over 5 min under anesthesia of santabarbara, took 5 volumes of blood from the inferior Vena cava in a plastic syringe, which contained one volume of 3.8% sodium citrate. Sample test drugs introduced orally one hour before the injection of collagen. Collected in this way the blood was diluted 20 times with Isotone II and subjected to centrifugation at 60g for 5 minutes Then the upper layer was again diluted with Isotone II to measure the number of platelets using sketchies ticlopidine hydrochloride (Dauchi Seiyaku Co. Ltd) and Cilostazol (Otsuka Pharmaceutical Co. Ltd).

II. Cardiotonic effect.

After bleeding, male Guinea pigs (Hartley type, 250-400 g) heart was removed and immediately immersed in nutrient solution (solution of Krebs-Henseleit: NaCl 118,4 mm 4,7 mm KCl, MgSO47H2About 1,18 mm CaCl22H2O 2.5 mm, KH2PO41.2 mm NaHCO324,9 mm, glucose of 11.1 mm), aerated with oxygen (containing 5% carbon dioxide). Then, to obtain a sample for testing, put aerated with oxygen nutrient solution in a laboratory cell with continuous aeration with oxygen. After a quick separation of the Atria and ventricle, the right ventricle has prepared the drug cocovideos muscles and hung him in the tub for bodies filled with aerated oxygen to the nutrient solution at a constant temperature 31aboutWith, and then applied tensile stress of 500 mg.

After 20 min after suspension of the drug cocovideos muscle nutrient solution was replaced, and after 40 min, and after watching for 20 min, in a cumulative way introduced isoproterenol (final concentration of 3 x 10-7M) to observe its effect on the contractile force of the muscle. After TRG is, the after observation for a further 20 min, cumulative method introduced sample test drugs. The effect that had each tested the drug on the contractile force was estimated based on relative changes (%) caused by the test drug, assuming that the difference of the magnitude of contractile force during the second injection of isoproterenol is 100% and was calculated concentration EU30(M) required for a 30% increase.

Measurement of contractile force was carried out by applying rectangular pulses [voltage: threshold value x 2 (V), length: 3 (MS), frequency: 1 (Hz)] on sokolinoy muscle through bipolar platinum electrodes from an electronic stimulator (hihon Kohden SEN-3201) to register the resulting voltage at the recording device using a wire strain gauge and F-D-grip.

As a control of cardio-tonic used milrinone (Wintrop Co. ).

III. Vasodilatory effect

Male rats (a type of white Japanese rats, 2-2 .5 kg) were subjected to anesthesia by intravenous injection of Nembutal [weight, kg x 0.5 + 0.5 ml] After bleeding learned thoracic aorta and put it immediately in nutrient rest the PO41.2 mm NaHCO324,9 mm, glucose of 11.1 mm), aerated with oxygen (containing 5% carbon dioxide). Then it was placed, for the purpose of preparation of the drug in laboratory cuvette filled with aerated oxygen to the nutrient solution, and fixing both ends of a blood vessel with pins in order to remove fat and connective tissue. Spiraling drug (width: 3 mm, length: about 1 cm) was cut out with scissors. Fixed bracket both sides of the drug, and hung him in the tub for bodies filled with aerated oxygen to the nutrient solution at a constant temperature of 37aboutWith, and then put to him tensile stress of 2 g

The stretching of the blood vessel were recorded using a recording device [hihon Kohden] by F-D-capture [hihon Kohden 611-T] and wire strain gauge [hihon Kohden AP-600G]

After suspension of a sample of the nutrient solution was changed after 20 and 40 minutes, watching each sample for 20 min (during which the tensile stress was 2 g). Then introduced norepinephrine (final concentration: 10-6M) and observed the condition of the blood vessel under the influence of the voltage. After the sample was observed within 20 min, penalty reductions introduced by cumulative method the sample of the tested drugs. After testing introduced papaverine (final concentration: 10-4M) to ensure complete relaxation.

The influence of the sample of the tested drugs on the reduction caused contractile agent, was evaluated by the relative changes (%) caused by introduction of the sample tested medications, under the assumption that the difference between the tensile force during the introduction contractile agent and after injection of papaverine is 100%

IV. The effect of anti-SRS-A (the effect of the expansion of the bronchi)

Medicine:

Sample test drugs used in the form of a solution in 100% dimethyl sulfoxide (DMSO, Wako Junyaku), Leukotriene D4(LTD4, Hetrafine) was diluted with distilled water.

Indomethacin (Indo, Sigma) was dissolved in 100% ethanol (EtOH, Comune Called). Aminophylline (AR, Sigma), histamine hydrochloride (His, Wako Junyaku) was dissolved in distilled water. Final concentration of DMSO and EtOH in the bath did not exceed, respectively, of 0.25% V/V and 0.1% vol/vol.

Method.

Had bled a Guinea pig weighing 300-450 g, and pulled the trachea. After removal of fat and connective tissue was cut into spiral strips with a width of about 2 mm and divided into 2-3 pieces, each to the 8 ml, containing the modified solution Tirade, aerated with a mixture of 95% O2+ 5% CO2at 37aboutWith, and to him put the load 1, the Relaxation of the muscles were recorded by a recorder (Yokogama Hokushin Electric, type 3066) using isotonic transducer (Nihon Kohden TD-112S).

A modified solution of Tyrode had the following composition (mm):

NaCl 1137, of 2.7 KCl, CaCl21,8, MgCl21,0, NaHCO320, NaH2PO4, 0,32, glucose 11.

The sample was kept for about 50-60 min, and then caused a reduction in the action of histamine hydrochloride (100 M). After reaching constant of the reaction the product was washed and kept for 20 to 30 minutes To the drug added indomethacin (5 M), and after incubation for 30 min caused a reduction of the drug added to it LTD4(30 nM). After the reaction became stable, cumulative introduced by the test drug. And finally, added the AR (1 mm) to achieve were expressed as percent relaxation, on the assumption that the relaxation under the action of AR was 100% and measured the concentration achieving 50% relaxation (EC50, M).

As control was used FPL-55712, known as the drug with the election of ant is s

I. the Effect of suppressing the aggregation of platelets.

1. Tests in vitro: (A) (B)

Table. 3-6 show the effect of suppressing the aggregation of platelets caused by the test compounds, which were estimated by the value of the IC50(M).

2. Tests in vivo.

(A) the Effect of suppressing the aggregation of platelets in rats is shown in table. 7.

(B) the Effect of suppressing the aggregation of platelets in Guinea pigs (1) are given in table. 8, 9.

The effect of suppressing the aggregation of platelets in Guinea pigs (2).

(C) Effect of inhibition of the reduction of mouse platelets are given in table.10.

II. Cardiotoniceski effect are given in table.11.

III. The vasodilator effect are given in table.12.

IV. The effect of anti-SRS-A is shown in table.12.

Possible application in industry.

As clearly follows from the above results, the compounds of this invention have excellent effect of suppressing aggregation of platelets, cardiotonic action, vasodilating action and counteraction against SRS-A. Thus, the compounds of this invention can be used as the problems hypertension, angina, heart failure and allergic conditions of the immediate type, including asthma.

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

< / BR>
where R1is hydrogen, an alkyl group WITH1- C4the group of General formula

-(CH2)nCO2R5,

where n = 1, 2, or 3;

R5is hydrogen or an alkyl group WITH1- C4,

R2group of the formula A1- Y1where AND1- alkylen1- C12with a straight or branched chain, Y1group CO2R5where R5has the specified values, cyano, phenoxy, thienyl, pyridyl

or a group of the General formula

< / BR>
where R7and R8independently is hydrogen, alkyl WITH1- C4, cyclohexyl, phenyl, or a group thiazolyl or thiadiazolyl or R7and R8together form alkylenes group2- C8which may be substituted by alkyl group WITH1- C3or phenyl group, or R7and R8together with the nitrogen atom to which they are attached, form morpholino ring,

or a group of the General formula

< / BR>
where R5has the specified values,

R9is an alkyl WITHBR>< / BR>
where R10and R11are independently hydrogen, halogen, C1- C4-alkyl, C1- C4-alkoxy, C1- C4-alkylthio, hydroxyl, C1- C4-alkanolamine,1- C4-alkanoyloxy or a group of the General formula NHSO2R9where R9has the specified values,

or a group of the General formula

< / BR>
where R13is hydrogen, R14is a phenyl group, or R13and R14together form alkylenes group2- C8,

or a group of the General formula

< / BR>
where R15is hydrogen or an alkyl group WITH1- C4, R16is an alkyl group WITH1- C4or R15and R16together form alkylenes group2- C8,

or a group of the General formula

< / BR>
where R17and R18is independently an alkyl group WITH1- C4or R17and R18together with the nitrogen atom to which they are attached, form pyrrolidino, piperidino, oxazolidine, optionally substituted oxopropoxy or they can form piperazinone, substituted on the other nitrogen atom of diphenylmethyl>R3is hydrogen or C1- C3-alkyl;

R4is hydrogen;

X is chlorine, bromine, hydrogen or cyano

AG - group of General formula

< / BR>
where j = 0 or 1;

R20is hydrogen, halogen or1- C4-alkoxygroup or a group of the formula

< / BR>
or a group of the General formula

< / BR>
where R21is hydrogen or C1- C4-alkoxygroup or a group of the General formula

< / BR>
where Z2and Z3is independently hydrogen, halogen, an alkyl group WITH1- C4or1- C7-alkoxy, the latter optionally substituted by phenyl, piperidinylcarbonyl or aminocarbonyl, while the amino group substituted WITH1- C4the alkyl and cyclohexyl,

or a group of the formula

< / BR>
provided that if in group A1- Y1Y1- phenyl, AND then1may not mean a methylene,

or their pharmaceutically acceptable salts.

2. Pharmaceutical composition having antithrombotic, inotropic, vasodilator and antagonistic towards mediator activity, containing derivative 3(2H)-pyridazinone and a pharmaceutically acceptable carrier, characterized in that it contains in cachestate 0.5 to 95 wt.%.

 

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