New derivatives of pyridazine and medicines containing them as effective ingredients

 

This invention relates to the derivatives of pyridazine, represented by the following formula (I):where R1represents C1-C6CNS group, C1-C6allylthiourea or halogen atom; R2denotes a hydrogen atom, a C1-C6CNS group, C1-C6allylthiourea or halogen atom; R3denotes a linear or branched C1-C6alkyl or C2-C9alkenylphenol group which may be substituted by a hydroxy-group, halogen atom, cyano, C3-C6cycloalkyl group, or phenyl or peredelnoj group which may have one to three substituent selected from a halogen atom, nitro group, amino group or pyridylcarbonyl, or carbamoyl group which may be substituted C1-C6alkyl group, hydroxyl-C1-C6alkyl group, pyridyl-C1-C6alkyl group or a C1-C6alkylthiophenes group; R4denotes a carboxyl group, a C1-C6alkoxycarbonyl group, carbamoyl or C1-C6architekturbuero group which may be substituted by a group or pyridyl-C1-C6alkyl group, an amino group which may be substituted1-C6alkoxycarbonyl group, phenyl-C1-C6alkoxycarbonyl group1-C6alkyldiphenyl-C1-C6alkoxycarbonyl group1-C5acyl group, With1-C6alkyl group, a phenyl-C1-C6alkyl group, pyridyl-C1-C6alkyl group or a C1-C6alkylsulfonyl group, or raidgroup, which may be substituted With1-C6alkyl group; and the dotted line indicates that the bond carbon-carbon bonds between position 4 and position 5 is a simple bond or a double bond; or its salt. The compounds of formula I possess inhibitory activity against the production of interleukin-1and can be used as an active ingredient of a medicinal product for the prevention and treatment of rheumatism or arthritis. The objects of the invention are also medicinal product having the above activity, and a method of treatment of a disease caused by stimulation of the production of interleukin-1such as rheumatism or arthritis. 3 S. and 7 xt-align:center; margin-top:2mm;">Claims

1. Derived pyridazine, represented by the following formula (1)

where R1stands With1-C6CNS group1-C6allylthiourea or halogen atom;

R2denotes a hydrogen atom, a C1-C6CNS group1-C6alkyl-togroup or halogen atom;

R3denotes a linear or branched C1-C6alkyl or C2-C9alkenylphenol group which may be substituted by a hydroxy-group, halogen atom, cyano, C3-C6cycloalkyl group, or phenyl, or peredelnoj group which may have one to three substituent selected from a halogen atom, nitro group, amino group or pyridylcarbonyl, or carbamoyl group which may be substituted With1-C6alkyl group, hydroxyl-C1-C6alkyl group, pyridyl-C1-C6alkyl group or a C1-C6alkylthiophenes group;

R4denotes the carboxyl group, With1-C6alkoxycarbonyl group, carbamoyl or1-C6architekturbuero group, the cat is1-C6alkyl group or pyridyl-C1-C6alkyl group, an amino group which may be substituted1-C6alkoxycarbonyl group, phenyl-C1-C6alkoxycarbonyl group1-C6alkyldiphenyl-C1-C6alkoxycarbonyl group1-C5acyl group, With1-C6alkyl group, a phenyl-C1-C6alkyl group, pyridyl-C1-C6alkyl group or a C1-C6alkylsulfonyl group, or raidgroup, which may be substituted With1-C6alkyl group; the dotted line indicates that the bond carbon-carbon bonds between position 4 and position 5 is a simple bond or a double bond;

or its salt.

2. Derived pyridazine or its salt under item 1, where the carbon-carbon bonds between position 4 and position 5 in the formula (1) is a double bond.

3. Derived pyridazine or its salt under item 1 or 2, where R1denotes a fluorine atom, a C1-C6CNS group or1-C6allylthiourea and R2denotes a hydrogen atom, a halogen atom or With1-C6CNS group.

4. Derived pyridazine or its salt under item 1, (4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-cyclopropylmethyl-4-ethylcarboxyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one, 2-(4-chlorocinnamoyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one or 2-(4-chlorocinnamoyl)-4-formylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one.

5. Drug, possess inhibitory activity against the production of interleukin-1which contains as an effective ingredient derived pyridazine or its salt according to any one of paragraphs.1-4.

6. Drug under item 5, which is a prophylactic or therapeutic agent for diseases caused by stimulation of the production of interleukin-1.

7. Drug under item 5, which is a prophylactic or therapeutic agent for rheumatism or arthritis.

8. Drug under item 5, further containing a pharmaceutically acceptable carrier.

9. Derived pyridazine or its salt according to any one of paragraphs.1-4 as an active ingredient of a medicinal product for the prevention or treatment of rheumatism or arthritis.

10. A method of treating diseases caused by trevose introduction to the patient, in need of such treatment, derived pyridazine or its salt according to any one of paragraphs.1-4.

 

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< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

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< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

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< / BR>
where R1- C1-C12-alkyl, linear or branched, if necessary monosubstituted monocyclic saturated or polyunsaturated carbocycles with 6 ring members, WITH6-aryl group and closed carbocyclic substituents on its part, if necessary, can be mono - or polyamidine R4; R5- monocyclic polyunsaturated carbocycles with 6 ring members, mono - or politeley atoms, halogen or a monocyclic polyunsaturated heterocycles with 6 ring members, one of which is N as heteroatom, mono - or politeley atoms of halogen; R2and R3can be hydrogen or HE, and at least one or both of the Deputy should be-HE; R4means-H, -OH, -F, -Cl, -J, -Br, -O-C1-C6-alkyl, -NO2; A -, or a bond, or -(CHOZ)m-(C= 0)-, and m= 0

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< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

A represents a group of the formula

< / BR>
where Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10< / BR>
where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

< / BR>
where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal

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