Derivatives pyrimidinediamine and fungicides for agriculture or horticulture

 

(57) Abstract:

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture based on them. In the compounds of General formula I a represents oxygen or sulfur, Q represents a cyano or the group COR7where R7means1-C6is an alkyl group, a C3-C6-cycloalkyl group which may be substituted by a halogen atom or WITH1-C6is an alkyl group WITH1-C6-halogenation group1-C6-alkoxygroup,2-C6-alkenylacyl,2-C6-alkyloxy or3-C6-cycloalkylation; R4represents a hydrogen atom, a C1-C6is an alkyl group, a C3-C6-cycloalkyl group or1-C6-halogenation group; R1, R2, RC, R5, R6mean hydrogen, C1-C6is an alkyl group and the other groups specified in the claims, or R2and R3together with the carbon atom to which they are attached, form an unsaturated 5 to 6 membered ring, or R5and R6together with the carbon atom to which they svazany, or form a 5-6-membered heterocyclyl group containing an oxygen atom or a sulfur atom as heteroatoms, and which may be substituted1-C6is an alkyl group. The invention also relates to a fungicide for agriculture or horticulture, comprising the above compounds as the active ingredient. 4 S. p. f-crystals, 26 PL.

The technical field

The present invention relates to new derivatives of pyrimidinediamine and containing them as active ingredients of the fungicides used in agriculture or horticulture.

Prior art

In the patent application of Japan, the first publication N Sho 63-132867 indicates that the fungicidal activity have derived aryloxyalkanoic acid. In the earlier application discloses compounds having 2-pyrimidinyl group without substituents in the aryl group; however, they do not show sufficient fungicidal activity. In addition, there are disclosed compounds having 4-pyrimidinyl group with substituents.

Recently it was found that the conventional fungicides do not exhibit sufficient activity due to the appearance after repeated data with environmental protection, it would be desirable to provide new fungicides, which can effectively fight against harmful fungi even at low concentrations. The present invention provides new derivatives of pyrimidinediamine exhibiting excellent fungicidal activity.

Therefore, the present inventors synthesized various new derivatives pyrimidinediamine and conducted intensive research aimed at the study of their influence on the biological activity of fungi. In the result, the inventors found that the new compounds in accordance with the present invention have a broad spectrum fungicidal activity and exhibit excellent fungicidal activity against pyricularia rice and similar diseases and at the same time not impede the necessary plant growth.

Description of the invention

The present invention provides derivatives of pyrimidinediamine represented by the formula (I)

< / BR>
where R1represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup,21-C6allylthiourea, C1-C6alkylsulfonyl group, C1-C6alkylsulfonyl group, C2-C6altertekhnogrupp,2-C6alinytjara,3-C6cycloalkylation, C1-C6alkylamino, di(C1-C6alkyl)amino group, halogen atom, phenyl group (which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or a halogen atom) or fenoxaprop (which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or a halogen atom),

R2represents a hydrogen atom, a C1-C6alkyl group, a C2-C6alkenylphenol group, C2-C6alkylamino group3-C6cycloalkyl group, C1-C4halogenating group2-C6halogenalkyls group, C1-C6alkoxygroup,2-C6alkenylacyl,2-C6alkyloxy,3-C6cycloalkylation, C1-C6alinytjara, C1-C6alkylamino, di(C1-C6alkyl)amino group, halogen atom or phenyl group (which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or a halogen atom),

R3represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup, (C1-C6alkyl)carbonyl group, (C1-C6alkoxy)carbonyl group, a halogen atom, a nitro-group or a cyano or

R2and R3together with the carbon atom to which they are linked, form a saturated 6-membered ring or an unsaturated 5-membered or 6-membered ring,

R4represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group or a C1-C4halogenating group

R5and R6independently represent a hydrogen atom, a C1-C6alkyl group, a C2-C6alkenylphenol group3-C6cycloalkyl group (which mo is 1-C6alkyl group, a C1-C6alkoxy, C1-C6alkyl group or a C1-C4halogenating group, or

R5and R6together with the carbon atom to which they are bound, form a 5-membered ~ 7-membered cycloalkyl group (which may be substituted C1-C6alkyl group) or heterocyclyl group (which may be substituted C1-C6alkyl group),

Q represents a cyano or a group of the formula-COR7[where R7represents a C1-C6alkyl group, a C3-C6cycloalkyl group (which may be substituted by a halogen atom or C1-C6alkyl group), C1-C4halogenating group, C1-C6alkoxygroup,2-C6alkenylacyl,2-C6alkyloxy or3-C6cycloalkylation]

And represents an oxygen atom or a sulfur atom, and fungicides for agriculture or horticulture, comprising as the main ingredient derived pyrimidinediamine.

The terms used in the present invention, is defined as follows. For example, in the crust 1 to 6 carbon atoms.

Used in this invention, the term "C1-C6alkyl group" means an alkyl group with straight or branched chain, including, for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, isopentyl group, neopentyl group, n-hexoloy group, isohexyl group, 3,3-dimethylbutyl group or a similar group.

As the term "C3-C6cycloalkyl group" can be mentioned, for example, cyclopropyl group, cyclopentenone group, tsiklogeksilnogo group or similar.

As the term "C3-C6cycloalkyl C1-C6alkyl group" can be mentioned, for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group or similar.

The term "C1-C4halogenation group" used in this invention to denote a halogen-substituted alkyl group with straight or branched chain, including, for example, formeterol group, chloromethylene group, bromatology group, deformational gruttadaurio group or similar.

The term "C2-C6Alchemilla group" used in this invention to denote alkenylphenol group with a straight or branched chain, including, for example, vinyl group, 1-propenyloxy group, allyl group, Isopropenyl group, 1-butenyloxy group, 2-butenyloxy group or similar group.

The term "C2-C6Alchemilla group" used in this invention to denote alkenylphenol group with a straight or branched chain, including, for example, etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 4-methyl-1-pantanillo group, 3-methyl-1-pantanillo group or similar group.

The term "halogen atom" is used here to denote a fluorine atom, chlorine atom, bromine atom or iodine atom.

The term "C1-C6alkoxygroup" is used in this invention to denote alkoxygroup straight or branched chain, including, for example, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, n-pentyloxy, isopentylamine, n-hexyloxy or p the Oia alkenylacyl straight or branched chain, including, for example, alliancegroup, isopropenylacetate, 2-butenyloxy or similar.

The term "C2-C6alkyloxy" is used in this invention to denote alkyloxy straight or branched chain, including, for example, 2-propenyloxy, 2-butenyloxy, 3-butenyloxy or similar.

As "C3-C6cycloalkylcarbonyl" in this invention may be mentioned, for example, cyclopropylamino, cyclopentyloxy, cyclohexyloxy or similar.

The term "C1-C4halogenosilanes" is used in this invention to denote a halogensubstituted alkoxygroup straight or branched chain, including, for example, formatexpr, dipterocarp, cryptometer, pentafluoropropyl or similar.

The term "C1-C6allylthiourea" is used in this invention to denote ancilliary straight or branched chain, including, for example, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, sec-butylthiourea, tert-butylthiourea, n-vexillographer or similar.

The term "C1-C6alkylsulfonyl group" used in this invention to denote alkylsulfonyl group with a straight or branched chain, including, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylphenyl group, n-butylsulfonyl group, isobutylamino group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-hexylaniline group or similar.

The term "C1-C6alkylamino" is used in this invention to denote alkylamino straight or branched chain, including, for example, methylaminopropyl, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-hexylamino or similar.

As the term "di(C

The term "(C1-C6alkyl)carbonyl group" is used in this invention to denote alkylcarboxylic group with a straight or branched chain, including, for example, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group or similar.

The term "(C1-C6alkoxy)carbonyl group" is used in this invention to denote alkoxycarbonyl group with a straight or branched chain, including, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-ventilatsioonile group, n-hexyloxymethyl group or similar.

The term "heterocyclyl group" used in this invention to denote a saturated tikililei group, including as a constituent atom, at least one oxygen atom or sulfur atom, which includes, for example, 3-oxalanilide group, 4-oxanilide group, 3-colaninno group, 4-dianilino the receiving may exist due to the presence in the molecule of one or more asymmetric carbon atoms, in the form of optical isomers. The present invention relates to the diastereomers, the enantiomers and their mixtures.

Preferred compounds represented by formula (I) in accordance with the present invention are those in which:

R1represents a hydrogen atom, methyl group, cyclopropyl group, methylthiourea, ethylthiourea, allyl-togroup, propargylation, a methoxy group, ethoxypropan, fenoxaprop or phenyl group,

R2represents a methyl group, ethyl group, isopropyl group, triptorelin group, chlorodifluoromethyl group, deformational group, dichloromethylene group, dibromomethyl group, a methoxy group, metalcorp or chlorine atom,

R3represents a hydrogen atom, methyl group, ethyl group, chlorine atom or bromine atom,

R4represents a hydrogen atom, methyl group or ethyl group,

R5represents a hydrogen atom, methyl group, ethyl group or n-sawn group

R6represents a methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, vtuu group, and

Q represents a cyano, acetyl group, propionyl group, methoxycarbonyl group or ethoxy-carbonyl group.

The following tables 1-15 lists the typical compounds represented by formula (I), in accordance with the present invention. However, it should be understood that the present invention is not limited to such compounds. Rooms compounds listed in the tables correspond to the numbers in the following description.

In the tables, "Me" means metal group, "Et" means ethyl group, n-WG" means n-through the group, i-Pr means isopropyl group, n-Bu" means n-boutelou group, "i-Bu" means isobutylene group, s-Bu" means second-boutelou group, "t-Bu" means tert-boutelou group, and "Ph" means a phenyl group. Therefore, Ph(4-C1)" means 4-chloraniline group

"Isomer A" is a diastereoisomer And configuration, "Isomer" is a diastereoisomer In configuration and Isomer M" is a mixture of diastereoisomer A-configuration and diastereoisomer In configuration. "Isomer RA" is a diastereoisomer A-configuration, where the acid group is an optically active group (R-configuratie group (R-configuration) and Isomer RM" is a mixture of diastereomers, where the acid group is an optically active group (R-configuration). "Isomer SA" is a diastereoisomer A-configuration, where the acid group is an optically active group (S-configuration). "Isomer SB" is a diastereoisomer In a configuration where the acid group is an optically active group (S-configuration) and Isomer SM" is a mixture of diastereomers, where the acid group is an optically active group (S-configuration). "Diastereoisomer And configuration" means iskopaemye the diastereoisomer allocated column chromatography on silica gel, high performance liquid chromatography or similar methods, whereas the diastereoisomer In configuration" means the highly polar diastereoisomer, selected by the above methods.

Compounds represented by formula (I) can be synthesized, for example, in accordance with the following methods of getting.

The method of obtaining 1 (see diagram 1 at the end of the description).

The compounds of formula (I) in accordance with the present invention can be obtained by reaction of derivatives pyrimidinemethanol acid represented by the formula (II) with amines, presented the Foundation. This reaction is usually carried out in a solvent, this solvent may be any solvent which does not disturb the reaction, for example hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene and the like solvents, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like solvents, ethers, such as diethyl ether, diisopropyl ether, dimethyl ether of ethylene glycol, tetrahydrofuran, dioxane and the like solvents, ketones, for example acetone, methyl ethyl ketone, methylisobutylketone, methyl isobutyl ketone and the like solvents, esters such as methyl acetate, ethyl acetate and the like, NITRILES such as acetonitrile, propionitrile and similar solvents, aprotic polar solvents such as dimethylsulfoxide, N, N-dimethylformamide, sulfolane and the like, and mixtures of solvents selected from the above solvents.

As the condensing agent can be called the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N, N'-dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolidin, 1-hydroxybenzotriazole, dimethylformamide or similar connection.

The base can be any base type commonly used in this type of reaction. So, for example, can be called the hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and the like, hydroxides of alkaline earth metals such as calcium hydroxide and the like, carbonates of alkali metals, for example sodium carbonate, potassium carbonate and the like compounds, organic bases such as triethylamine, trimethylamine, N,N-dimethylaniline, pyridine, N-methylpyridine, 1,5-diazabicyclo[4.3.0] non-5-ene (DBN), 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) and the like compounds, and preferably tertiary amines, such as triethylamine, pyridine, N-methylpiperidine and similar compounds.

This reaction is carried out at a temperature in the range from -50oWith up to 150oC and preferably at a temperature in the range of 0oWith up to 60oC. the reaction Time is preferably in the range from 1 to 30 hours.

Next will be explained the method of synthesis of each of the original substance.

Compounds represented by formula (II) can be synthesized, for example, in accordance with ways as seen below n in formula (II), can be obtained, for example, by reacting pyrimidine derivatives represented by the formula (IV) derivatives of esters alkanovykh acids represented by the formula (VI), in the presence of a base to obtain derivatives of esters pyrimidinediamine acids represented by the formula (V), and subsequent hydrolysis derivatives of esters pyrimidinediamine acids.

In accordance with the above reaction schemes, reaction of pyrimidine derivatives represented by the formula (IV) with a derivative of ester represented by the formula (VI), carried out usually in a solvent, this solvent may be any solvent which does not disturb the reaction, for example hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene and the like solvents, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like solvents, ethers, such as diethyl ether, diisopropyl ether, dimethyl ether of ethylene glycol, tetrahydrofuran, dioxane and the like solvents, ketones, for example acetone, methyl ethyl ketone, IU the silts for example acetonitrile, propionitrile and similar solvents, aprotic polar solvents such as dimethylsulfoxide, N,N-dimethylformamide, sulfolane and the like, and mixtures of solvents selected from the above solvents.

The base can be any base type commonly used in this type of reaction. So, for example, can be called inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, potassium hydride and the like, or organic bases such as triethylamine, trimethylamine, N,N-dimethylaniline, pyridine and the like.

This reaction is carried out at a temperature in the range from -50oWith up to 150oC and preferably at a temperature in the range of 0oWith up to 60oC. the reaction Time is preferably in the range from 1 to 30 hours.

The reaction of obtaining derivatives pyrimidinemethanol acid represented by the formula (II), derivatives via hydrolysis of esters pyrimidinediamine acids represented by the formula (V), carried out usually in a solvent, this solvent may be any solvent which does not interfere with producatorului ether, diisopropyl ether, dimethyl ether of ethylene glycol, tetrahydrofuran, dioxane and the like solvents, ketones, for example acetone, methyl ethyl ketone, methylisobutylketone, methyl isobutyl ketone and the mixture of solvents containing solvents selected from the above.

The base can be any base type commonly used in this type of reaction. So, for example, can be called inorganic bases such as sodium hydroxide, potassium hydroxide and the like bases.

This reaction is carried out at a temperature in the range from -50oWith up to 150oC and preferably at a temperature in the range of 0oWith up to 60oC. the reaction Time is preferably in the range from 1 to 30 hours.

Compounds represented by formula (IV) can be synthesized, for example, in accordance with known methods, such as chlorination of hydroxypyrimidine using phosphorus oxychloride (see Tetrahedron, Vol. 35, R. 2087, 1979; or Journal of Heterocycllc Chemistry, Vol. 20, p. 219, 1983).

Compounds represented by formula (III) can be obtained, for example, with the use of ketones, sodium cyanide and ammonium chloride in accordance with the method Strecker (Striker), which is disclosed in: Organic S is m scheme 3 in the end of the description).

The compounds of formula (I-1) in accordance with the present invention can be obtained by the reaction of pyrimidine derivatives represented by the formula (VII), with derivative alcanada represented by the formula (VIII) in the presence of a base. This reaction can be performed in a solvent, this solvent may be the same solvent, which is described in the production method of 1, and which does not interfere with the reaction.

The base can be any base type commonly used in this type of reaction. So, for example, can be called inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, potassium hydride and the like, or organic bases such as triethylamine, trimethylamine, N,N-dimethylaniline, pyridine and the like.

This reaction is carried out at a temperature in the range from -50oWith up to 150oC and preferably at a temperature in the range of 0oWith up to 60oC. the reaction Time is preferably in the range from 1 to 30 hours.

Participating in this reaction, the compound represented by formula (VII) can be PAL.

In addition, compounds represented by formula (VIII) can be obtained, for example, in accordance with the reaction of halogenated alkanolamines amine derivative represented by the formula (III).

The method of obtaining 3 (see diagram 4 in the end of the description).

The compounds of formula (I-2) in accordance with the present invention can be obtained by the reaction of pyrimidine derivatives represented by the formula (IV) with a derivative of alcanada represented by the formula (IX) in the presence of a base. This reaction can be performed in a solvent, this solvent may be the same solvent, which is described in the method of obtaining 1 and which does not interfere with the reaction.

As a basis you can use the same base, which was described in the production method of 2.

This reaction is carried out at a temperature in the range from -50oWith up to 150oC and preferably at a temperature in the range of 0oWith up to 60oC. the reaction Time is preferably in the range from 1 to 30 hours.

Participating in this reaction, the compound represented by formula (IX) can be obtained, for example, diallylammonium prostaglandin formula (VIII), with sodium acetate.

The best ways of carrying out the invention

In the following description of the invention examples of preparing compounds in accordance with the present invention.

Example obtain 1

Synthesis of 2-(5-chloro-6-ethylpyrimidine-4-yloxy)-N-(1-cyano-1,2-dimethylpropyl)ndimethylacetamide (compound a-7)

To a solution containing 2-(5-chloro-6-ethylpyrimidine-4-yloxy)acetic acid (1.0 g) dissolved in methylene chloride (50 ml) at room temperature add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the mixture is stirred for 10 minutes. Then to the mixture is added 2-amino-2,3-dimethylbutyramide (0.5 g) and the reaction mixture is stirred for 3 hours at room temperature. After completion of the reaction to the resulting mixture, water is added and the methylene chloride layer is washed with water and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove methylene chloride. The residue is purified column chromatography on silica gel, thus obtain 0.8 g of target compound having a refractive index equal to 1,5166 (20oC).

Reference example 1-a

Synthesis of ethyl 2-(5-chloro-6-ethylpyrimidine-4-yloxy)acetate

60% sodium hydride (0.5 g) probyvala drops add ethylglycol (1.2 g) and the mixture is then stirred for one hour at room temperature. Then it added dropwise 4,5-dichloro-6-ethylpyrimidine (2.0 g) and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction to the reaction liquid add water. The organic layer is extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove the ethyl acetate. The residue is purified column chromatography on silica gel, thus obtain 2.6 g of the desired product in the form of butter.

Reference example 1-b

Synthesis of 2-(5-chloro-6-ethylpyrimidine-4-yloxy)acetic acid (Intermediate compound 2)

In ethanol (50 ml) was dissolved ethyl 2-(5-chloro-6-ethylpyrimidine-4-yloxy)acetate (2.6 g). To it added dropwise a solution containing sodium hydroxide (0.7 g) and the mixture is then stirred for one hour at room temperature. After completion of the reaction to the reaction liquid add water and then acidified with citric acid. The organic layer is extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove the ethyl acetate. The resulting crystals are washed with hexane, and thus obtain 1.4 g of the desired product having a melting point of 158oWith up to 159oC.

the compounds of the compounds in accordance with the present invention, receive in a manner similar to that described in reference example 1 and reference example 1-b.

Example of getting 2

Synthesis of methyl 2-(1-(5-chloro-6-cryptomaterial-4-yloxy)ethylcarbodiimide)-2,3-dimethylbutanoate (Compound A-93)

To a solution containing 2-(5-chloro-6-cryptomaterial-4-yloxy) propionic acid (1.4 g) dissolved in methylene chloride (20 ml) at room temperature add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1 g) and the mixture is stirred for 10 minutes. Then to the mixture is added methyl 2-amino-2,3-dimethylbutyryl (0.8 g) and the reaction mixture is stirred for 4 hours at room temperature. After completion of the reaction to the resulting mixture, water is added and the methylene chloride layer is washed with water, then dried over anhydrous magnesium sulfate. Under reduced pressure to remove methylene chloride. The residue is purified column chromatography on silica gel, thus obtain 1.3 g of the target compound, having a melting point of from 85oWith up to 86oC.

Reference example 2-a

Synthesis of ethyl 2-(5-chloro-6-cryptomaterial-4-yloxy)propionate

60% sodium hydride (0.6 g) was washed with hexane and then suspended in tetradium the mixture is stirred for one hour at room temperature. Then to the mixture being in the bath, cooled with ice, added dropwise 4,5-dichloro-6-cryptomaterial (3.1 g) and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction to the reaction liquid add water. The organic layer is extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove the ethyl acetate. The residue is purified column chromatography on silica gel, thus obtain 3.5 g of the desired product in the form of butter.

Reference example 2-b

Synthesis of 2-(5-chloro-6-cryptomaterial-4-yloxy)propionic acid (Intermediate compound 6)

In 1,4-dioxane (20 ml) was dissolved ethyl 2-(5-chloro-6-cryptomaterial-4-yloxy)propionate (3.5 g). In the bath, cooled with ice, add a solution containing sodium hydroxide (0.8 g) dissolved in water (10 ml), and then the mixture is stirred for one hour at room temperature. After completion of the reaction to the reaction liquid add water. Then the reaction liquid is acidified with citric acid. The organic layer is extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove the ethyl acetate. The obtained crystals UP>oC.

Example of getting 3

Synthesis of 2-(5-chloro-6-cryptomaterial-4-yloxy)-N-(1-cyanocyclohexyl)propionamide (Compound a-80)

To a solution containing 2-(5-chloro-6-cryptomaterial-4-yloxy)propionic acid (1.0 g) dissolved in chloroform (30 ml) at room temperature add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1 g) and the mixture is stirred for 30 minutes. Then to the mixture was added 1-amino-cyclopentanecarbonitrile (0.4 g) and the reaction mixture is stirred for 10 hours at room temperature. After completion of the reaction to the resulting mixture, water is added and the chloroform layer washed with water, then dried over anhydrous magnesium sulfate. Under reduced pressure to remove the chloroform. The residue is purified column chromatography on silica gel, thus obtain 0.6 g of the target compound, having a melting point of 172oWith up to 174oC.

Example 4

Synthesis of 2-(5-chloro-2-methyl-6-cryptomaterial-4-yloxy)-N-(1-cyano-1,2,2-trimethylpropyl)propionamide (Compound A-151, a-152)

To a solution containing 2-(5-chloro-2-methyl-6-cryptomaterial-4-yloxy)propionic acid (1/0 g) dissolved in tetrahydrofuran (30 ml), under whom the t for 30 minutes. Then to the mixture is added 2-amino-2,3,3-trimethylbutyramide (0.5 g) and the reaction mixture is stirred for 10 hours at room temperature. After completion of the reaction to the resulting mixture, water is added, extracted with ethyl acetate the organic layer and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove the ethyl acetate. The residue is purified column chromatography on silica gel, thus obtain 0.3 g of diastereoisomer A-configuration, having a melting point of 133oWith up to 134oWith, and 0.2 g of diastereoisomer In configuration, having a melting point of 137oWith up to 139oC.

Example of getting 5

Synthesis of 2-(5-chloro-6-isopropylpyrimidine-4-ylthio)-N-(1-cyano-1,2-dimethylpropyl)propionamide (Compound b-17)

60% sodium hydride (0.1 g) was washed with hexane and then suspended in dimethylformamide (20 ml). To the suspension is added dropwise 5-chloro-6-isopropyl-4-mercaptopyrimidine (0.2 g) and the mixture is then stirred for one hour at room temperature. Then it added dropwise N-(1-cyano-1,2-dimethylpropyl)-2-bromopropionate (0.3 g) and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction to the reaction gidha. Under reduced pressure to remove the ethyl acetate. The residue is purified column chromatography on silica gel, thus obtain 0.3 g of the desired product having a melting point of 73oWith up to 75oC.

An example of obtaining 6

Synthesis of 2-(2-allylthio-6-cryptomaterial-4-yloxy)-N-(1-cyano-1,2-dimethylpropyl)propionamide (Compound A-251)

In tetrahydrofuran (30 ml) was dissolved N-(1-cyano-1,2-dimethylpropyl)-2-hydroxypropionate (1.0 g). To the solution was added 60% sodium hydride (0.2 g) and the mixture is then stirred for 30 minutes at room temperature. Then to the mixture is added 2-allylthio-4-chloro-6-cryptomaterial (0.7 g) and then the reaction mixture is stirred for 6 hours at room temperature. After completion of the reaction to the reaction liquid add water. Then extracted with ethyl acetate the organic layer and dried over anhydrous magnesium sulfate. Under reduced pressure to remove the ethyl acetate. The residue is purified column chromatography on silica gel, thus obtain 1.1 g of the desired product having a melting point of 96oWith up to 98oC.

Example of getting 7

Synthesis of 2-(5-chloro-2-methyl-6-cryptomaterial-4-yloxy)-N-(1-isopropyl-1-methyl-2-oxoprop is)propionic acid (0.9 g), dissolved in dichloromethane (20 ml) at room temperature add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.7 g) and the mixture is stirred for 10 minutes. Then to the mixture is added 3-amino-3,4-dimethyl-2-pentanon (0.4 g) and the reaction mixture is stirred for 3 hours at room temperature. After completion of the reaction to the resulting mixture, water is added and the dichloromethane layer is washed with water and then dried over anhydrous magnesium sulfate. Under reduced pressure to remove dichloromethane. The residue is purified column chromatography on silica gel, thus obtain 0.8 g of the desired product having a melting point of 124oWith up to 126oC.

Fungicides for agriculture or horticulture in accordance with the present invention comprise as active ingredients derived pyrimidinediamine represented by the formula (I). When the compounds in accordance with the present invention are used as fungicides for agriculture or horticulture, connections, acting as active ingredients, depending on the purpose, can be appropriately formulated, i.e. included in the formulations. Usually antiuniverse-active substance and similar substances. After this mixture in a known manner formulate, for example, a fine powder (dust), wettable powder, emulsifiable concentrate, pellets or similar forms.

As a suitable carrier materials used in the composition, can be called solid carriers such as talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, slaked lime, siliceous sand, ammonium sulfate, urea or similar substances; and liquid carriers such as isopropyl alcohol, xylene, cyclohexanone, methylnaphthalene and the like substances. As surfactants and dispersants can be named, for example, dentalinsuranceplan, esters of alcohol and sulphuric acid, alkylarylsulfonate, ligninsulfonate, esters of polyoxyethyleneglycol, alkylacrylate esters of polyoxyethylene, polyoxyethylenesorbitan-monoalkylated and similar substances. As auxiliary substances can be called carboxymethylcellulose and similar substances. Formulated fungicide for agriculture or horticulture in accordance with the present invention may be applied by spraying after appropriate dilution, or may be applied directly.

Fungica the spray stem and leaf parts of plants, soil and immersion. The content of the active ingredient is chosen such that is necessary. While obtaining fine powder or granules is preferred concentration of active ingredient 0.1% by weight to 20% by weight. For concentrates, emulsions or wettable powders, the preferred concentration of active ingredient is from 5% by weight to 80% by weight.

The application dose of fungicide for agriculture or horticulture in accordance with the present invention may vary depending on the type of connection, type of pest or diseases against which the struggle against the causes of pest or disease, the extent of the damage plants, environmental conditions, form of drug used and similar circumstances. When fungicides for agriculture or horticulture of the present invention is applied directly in the form of fine powder or granules, it is recommended that the application dose of the active ingredient was accordingly selected in the range from 0.1 g to 5 kg/10 ar and preferably in the range of from 1 g to 1 kg/10 ar. When the fungicides of the present invention are in the form of a liquid ingredient was accordingly selected in the range from 0.1 frequent. per million to 10,000 frequent. per million (0.1 mg/l to 10 g/l) and preferably in the range from 1 frequent. per million up to 3000 frequent. per million (1 mg/l to 3 g/l).

Using fungicides of the present invention, which are used in agriculture or horticulture, it is possible to combat plant diseases caused by pathogenic fungi of the Oomycetes, Ascomycetes, Deuteromycetes and Basidiomycetes. The following are examples of fungi that are not limited to these fungi: Pseudoperonospora, for example fungi pathogens downy mildew (Pseudoperonospora cubensis), Sphaerotheca, for example fungi pathogens powdery mildew (Sphaerotheca luliginea), Venturia, for example fungi pathogens of Apple scab (Venturia inaequalis), Pyricularia, such as fungi, bacteria piricularia rice (Pyricularia oryzae), Gibberella, for example fungi pathogens "Bakanae" (Gibberella fujikuroi), Botrytis, such as fungi pathogens grey mold (Botrytis cinerea), Alternaria, for example fungi pathogens spot Sarepta mustard (Alternaria brassicicola), Rhizoctonia, for example fungi-rot pathogens of cereal flakes of rice (Rhizoctonia solani) and Puccinia, for example fungi pathogens rust (Puccinia recondita).

In addition, the compounds according to the invention can be applied individually or in combination with other women fungicidezyban typical examples of formulations of drugs, in which all "%" represents% by weight.

Example composition 1: a Fine powder

2% of Compound a-1, 5% of diatomaceous earth and 93% of clay uniformly mixed and ground into a fine powder.

Example composition 2: Wettable powder

50% of Compound a-7, 45% of diatomaceous earth, 2% dinaftiletilena sodium and 3% ligninsulfonate sodium uniformly mixed and pulverized in a wettable powder.

Example of compound 3: emulsifiable Concentrate

30% of Compound A-12, 20% of cyclohexanone, 11% alkylsilanes ester of polyoxyethylene, 4% of Las calcium and 35% of methylnaphthalene uniformly emuleret, while receiving emulsifiable concentrate.

Example of compound 4: Granules

5% of Compound B-5, 2% sodium salt of sulfate ester of lauric alcohol, 5% ligninsulfonate sodium, 2% carbon-simmilarly and 86% of clay are mixed and milled. To the crushed mixture is added water in the amount of 20% calculated on the total weight of the powdered mixture. The resulting mixture is stirred and molded into pellets ranging in size from 14 to 32 mesh mesh by extrusion granulator and then dried for formation of the desired granules.

Next, with reference to the examples ispytani the present invention. In the examples of the test as a comparative compound used is N-(1-cyano-1,2-dimethylpropyl)-2-(pyrimidine-2-yloxy)propionamide, disclosed in the patent application of Japan, the first publication N Sho. 63-132867.

Example test 1

Test preventive action of fungicides on pyricularia rice (Pyricularia oryzae)

Seeds of rice (variety: Aichi Asahi) seeded in porcelain pots with a diameter of 7 cm at the seeding rate of 15 seeds per pot. In the greenhouse provide the germination of seeds and their growth over time from 2 to 3 weeks. Wettable powder prepared in accordance with example composition 2, dilute with water to the concentration of the active ingredient 500 frequent. a million and then the resulting aqueous drug sprinkle rice seedlings at the stage of development of the 4-th sheet at the rate of 10 ml/pot. After drying in air shoots inoculant by spraying conidiospore suspension fungi pathogens piricularia rice (ricularia oryzae) and immediately placed for 24 hours in a humid chamber at 25oAnd then in a greenhouse. On the fifth day after inoculation calculate the amount of damage on the 4th sheet. In accordance with equation 1 calculates the degree of activity in combating fungi-vazbu, is shown in tables 18-21.

Equation 1

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Sample test 2

The test application in flooded conditions on pyricularia rice (Pyricularia oryzae).

Seeds of rice (variety: Aichi Asahi) on the development phase 1.5 sheet transplanted into 4 provisions in white porcelain pots with a diameter of 9 cm at the seeding rate of 3 sprout at each location in the pot. In the greenhouse provide the germination of seeds and their growth. When the seedlings will grow and reach the development phase 2.5 leaves, in irrigation water, in a pot, bring prepared in accordance with example composition 2 wettable powders, so that the concentration of active ingredient was 300 g/10 ar. 10 days after treatment, the seedlings inoculant by spraying conidiospore suspension fungi pathogens piricularia rice (Pyricularia oryzae) and immediately placed for 24 hours in a humid chamber at 25oAnd then in a greenhouse in order to cause disease. On the fifth day after inoculation calculate the amount of damage on the sheet, which at the time of inoculation is the most Mature stage of growth. In accordance with Equation 1 calculates the degree of activity suppression. The evaluation results obtained in the CE is th action against powdery mildew of wheat

9 Seeds of wheat (variety: Norin-61-go} were inoculated each in a separate PVC pot 9 cm x 9 cm, were grown in a greenhouse for 8 days, then was treated with aqueous solutions, wettable powders of 10 ml per pot, prepared in accordance with the composition of Example 2 at a concentration of active ingredients 500 ppm and dried in the air. Then the seedlings were inoculable disputes Erysiphe qraminis held in suspension, and placed in a greenhouse at a temperature of 25-30oC. within 10 days after inoculation were observed total infected area of the first leaves in each pot and were evaluated in accordance with standards specified in table A. the Results are presented in table Century.

Test preventive actions against Apple scab

5 Apple Seeds (variety: Kogyoku) were inoculated each in a separate PVC pot 9 cm x 9 cm, were grown in a greenhouse for 20 days. Shoots of Apple trees with 4 leaves were treated with aqueous solutions, wettable powders of 20 ml per pot, prepared in accordance with the composition of Example 2 at a concentration of active ingredients 500 ppm and dried in the air. Then the seedlings were inoculable disputes Venturia inaequalis, in suspension, and placed for 48 hours in the wet is after inoculation were observed total infected area of the top two from infected leaves and evaluated in accordance with the standards specified in Table A. the Results are presented in Table C.

1. Derived pyrimidinediamine represented by the formula (I)

< / BR>
where R1represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup,2-C6alkenylacyl, C2-C6alkyloxy,3-C6cycloalkylation, C1-C6allylthiourea, C1-C6alkylsulfonyl group, C1-C6alkylsulfonyl group, C2-C6altertekhnogrupp,2-C6alinytjara,3-C6cycloalkylation, halogen atom, phenyl group which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or halogen atom, or fenoxaprop, which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or a halogen atom;

R2represents a hydrogen atom, a C1-C6cycloalkyl group, C1-C4halogenating group2-C6halogenalkyls group, C1-C6alkoxygroup,2-C6alkenylacyl,2-C6alkyloxy,3-C6cycloalkylation, C1-C4halogenlampe, C1-C6allylthiourea,2-C6altertekhnogrupp, C2-C6alinytjara, halogen atom or phenyl group which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or a halogen atom;

R3represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup, (C1-C6alkyl)carbonyl group, (C1-C6alkoxy)carbonyl group, a halogen atom, a nitro-group or a cyano,

or R2and R3together with the carbon atom to which they are attached, form an unsaturated 5-membered or 6-membered ring;

R4represents a hydrogen atom, a C1-C6alkyl, Grupp>6independently represent a hydrogen atom, a C1-C6alkyl group, a C2-C6alkenylphenol group3-C6cycloalkyl group which may be substituted by a halogen atom or C1-C6alkyl group, a C3-C6cycloalkyl C1-C6alkyl group, a C1-C6alkoxy, C1-C6alkyl group or a C1-C4halogenating group, R5and R6together with the carbon atom to which they are bound, form a 5-membered ~7-membered cycloalkyl group which may be substituted C1-C6alkyl group, or a 5-membered or 6-membered heterocyclyl group containing an oxygen atom or a sulfur atom as a heteroatom, which may be substituted WITH1-C6alkyl group;

Q represents a cyano or a group of the formula-COR7where R7represents a C1-C6alkyl group, a C3-C6cycloalkyl group which may be substituted by a halogen atom or C1-C6alkyl group, a C1-C4halogenating group, C1-C6alkoxygroup,2-C6alkenylacyl,2-C6alkyloxy.

2. Derived pyrimidinediamine represented by the formula (I)

< / BR>
where R1represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup, C2-C6alkenylacyl, C2-C6alkyloxy,3-C6cycloalkylation, C1-C6allylthiourea, C1-C6alkylsulfonyl group, C1-C6alkylsulfonyl group, C2-C6altertekhnogrupp, C2-C6alinytjara,3-C6cycloalkylation, halogen atom, phenyl group which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or halogen atom, or fenoxaprop, which may be substituted C1-C6alkyl group, a C1-C4halogenoalkanes group, C1-C6alkoxygroup, a cyano, a nitro-group or a halogen atom;

R2represents a C1-C6alkyl group, a C2-C6alkenylphenol group2-C6and the/SUB>-C6halogenalkyls group, C1-C6alkoxygroup, C2-C6alkenylacyl,2-C6alkyloxy,3-C6cycloalkylation, C1-C4halogenlampe, C1-C6allylthiourea,2-C6altertekhnogrupp,

C2-C6alinytjara or halogen atom;

R3represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup, a halogen atom or a cyano,

or R2and R3together with the carbon atom to which they are attached, form an unsaturated 5-membered or 6-membered ring,

R4represents a hydrogen atom, a C1-C6alkyl group or a C3-C6cycloalkyl group

R5and R6independently represent a hydrogen atom, a C1-C6alkyl group, a C2-C6alkenylphenol group3-C6cycloalkyl group which may be substituted by a halogen atom or C1-C6alkyl group, a C1-C6alkoxy, C1-C6alkyl group or a C1-C1
-C6alkyl group, or a 5-membered or 6-membered heterocyclyl group containing an oxygen atom or a sulfur atom as a heteroatom, which may be substituted C1-C6alkyl group;

Q represents a cyano or a group of the formula-COR7where R7represents a C1-C6alkyl group, a C3-C6cycloalkyl group which may be substituted by a halogen atom or C1-C6alkyl group, a C1-C4halogenating group, C1-C6alkoxygroup,2-C6alkenylacyl,2-C6alkyloxy or3-C6cycloalkylation;

And represents an oxygen atom or a sulfur atom.

3. Derived pyrimidinediamine represented by the formula (I)

< / BR>
where R1represents a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group, C1-C4halogenating group, C1-C6alkoxygroup, C1-C6allylthiourea,2-C6altertekhnogrupp,2-C6alinytjara, halogen atom, phenyl group Il is talkingnow group, C1-C6alkoxygroup, C1-C6allylthiourea or halogen atom;

R3represents a hydrogen atom, a C1-C6alkyl group or a halogen atom,

R4represents a hydrogen atom or a C1-C6alkyl group;

R5and R6independently represent a hydrogen atom, a C1-C6alkyl group, a C3-C6cycloalkyl group or a C1-C4halogenating group, R5and R6together with the carbon atom to which they are bound, form a 5-membered ~7-membered cycloalkyl group which may be substituted C1-C6alkyl group,

Q represents a cyano or a group of the formula-COR7where R7represents a C1-C6alkyl group, a C3-C6cycloalkyl group or a C1-C6alkoxygroup;

And represents an oxygen atom or a sulfur atom.

4. Fungicide for agriculture or horticulture, comprising as an active ingredient derived pyrimidinediamine on PP.1, 2 or 3.

 

Same patents:

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia

The invention relates to a new crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane hydrofolate, method thereof, pharmaceutical compositions on the basis and method of reducing or preventing the rarefaction of bone, including the introduction to the patient an effective amount of the specified new connection

The invention relates to a new method of producing compounds of the formula I

< / BR>
where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to substituted chromalusion (thio)ureas of the formula (I):

< / BR>
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;

R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;

Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

A denotes the residue of a saturated or unsaturated lactam of the formula:

< / BR>
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
and their physiologically acceptable salts

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione
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