Derivatives of 2-[4-(4-azolylmethyl)-1-piperazinil]-pyrimidine or their physiologically acceptable salts, method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine, as having anxiolytic or soothing activity. The essence of the invention: derivatives of 2-[4-(4-azolylmethyl)-1-piperazinil] pyrimidine of the formula I

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in which X2- CR2where R2is hydrogen, halogen;

X4- N, CR4where R4is hydrogen,

X5- N or CR5where R5- ness. alkyl;

R3- halogen or their physiologically acceptable salts;

The method of producing compound I: carry out the oxidation of 5-benzyloxy-2-dimethylpyrimidine in the appropriate sulfon, replace radicalisation piperazine, the product is injected into the interaction with dibromobutane and the resulting methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere (4,5) decane condense with an azole of the formula

and the resulting product will unlock. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and at least one compound of formula I in an amount of from 2 to 20 mg 3 c. and 1 C.p. f-crystals, 1 Il.

The invention relates to new derivatives of 2-[4-(4-azolylmethyl)-1-piperazinil] -pyrimidine of the General formula I, to the way they are received, as well as containing their headlights is employed, the nitrogen atom or the group C-R2X4represents a nitrogen atom or a group C-R4X5represents a nitrogen atom or a group C-R5and R2, R3, R4and R5identical or different, represent a hydrogen atom, halogen, a radical is a lower alkyl, a nitro radical, a hydroxy radical, an alkoxy radical, a cyano radical, a carboxyl radical, carboxamide radical, the radical of alkylcarboxylic, the aryl radical, the radical of sulfonamide, radical amino or substituted amino.

The alkyl groups of the above-mentioned radicals are mainly groups of the lower Akilov straight or branched chain with C1-C6. Under the aryl mean mainly the phenyl radical, substituted if necessary, or aromatic heterocycle containing 5 to 6 links and at least a nitrogen atom.

Compounds according to the invention can be used in the pharmaceutical industry as intermediates for the synthesis for the preparation of pharmaceutical compositions.

There are various cyclic amides with anxiolytic activity, derivatives of arylpiperazines General formula II

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such as buspirone (Drugs of the Future, 1976, 1, 409), gepirone (Drugs of tht Future, 1985, 10, 456), IPS is R2listed below for each of them:

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Also known class of aryl-(o-heteroaryl)-piperazinil-alkylation used as dibenzodiazepine agents for the treatment of States of fear (European patents NN EP 382637, 497659 and 502786). In addition, these compounds also used to treat other behavioral disorders (European patents NN 429360 and 497658). Some of the most interesting compounds are azoles, substituted in 1-position by a group pyrimidinyl-piperazinil-butyl, formula I, in which R1represents a hydrogen atom and X2X4X5, R2, R3, R4and R5have the above values.

A particularly interesting connection is lesopitron (E-4424), the compound of General formula I, in which R1represents a hydrogen atom, X2represents a group CR2X4represents a group CR4X5represents a nitrogen atom, R2and R4represent hydrogen and R3is chlorine. It was found that lesopitron has a very wide and more potent activity profile than buspiron or ipsapirone (cf. B. Costall and other J. Pharmacol. Experimental Therapeutics, 1992, 262, 90).

Indicates that the connection is One of the metabolites is pyrimidyl-piperazine of the formula III

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compound that exhibits activity as a biochemical and pharmacological, as described in numerous scientific publications, including as examples, mention the following: E. Tatarczynska and other Pol. J. Pharm Pharmacol. 1989, 41, 51; A. Diaz-Marot and others J. Chromatogr. 1989, 490, 470; S. Caccia, etc. Acta Pharm. Jugosl., 1990, 40, 441; Nocon, H. and others, J. Pharm. Pharmacol. 1990, 42, 642.

Another metabolite of the above-mentioned compounds of General formula II represents the corresponding 5-hydroxy derivative of General formula II in which R1means a hydroxyl radical and R2has the above-mentioned values. In contrast to what happens with compound III, it was shown that the compounds of General formula II in which R1represents the radical hydroxide, are biologically inactive. This behavior is usually observed when gidroksilnuyu aromatic compounds in metabolic process (for example, Drug Metabolism. Chemical and Biochemical Aspects. B. Testa et P. Jenner, Marcel Dekker Inc. New York, 1976). As the bibliography related to the biological inactivity of compounds II in which R1represents a hydroxyl radical and R2has the above values, you can call: R. E. Gammans, etc. The American Journal of Medicine, 1986, 80(3B), 41; C. P. Vander Maelen and other Eur. J. Pharm34.

Now found that the new derivatives of 2-[4-(4-azolylmethyl)-1-piperazinil] -5-hydroxypyrimidine General formula I, in which R1represents a hydroxyl radical, and X2X4X5, R2, R3, R4and R5have the above values, and which are the subject of the invention are metabolites of compounds described in the patents of the applicant (EP 382637 and EP 497659) and having unexpectedly biological activity in relation to the Central nervous system, in particular, anxiolytic and calming effect, allowing their use in therapy for the treatment of diseases that affect the Central nervous system of mammals.

New derivatives of General formula I, in which R1represents a hydroxyl group and X2X4X5, R2, R3, R4and R5have the above values, can be obtained according to the invention the following reaction scheme:

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The original product is a 5-benzyloxy-2-methylthiopyrimidin IV, which can be obtained on the basis of chloride benzyloxyethyl, the sequence of reactions described by J. H. Chesterfield and others J. Chem. Soc., 1960, 4590, and D. T, Hurst and others J. Chem. Soc., 1965, 7116.

The connection is Inoi acid in water add 15,76 g (67,9 mmol) 5-benzyloxy-2-dimethylpyrimidine in 240 ml of chloroform. Carry out reflux the mixture for 5 hours, cool and add a saturated solution of acid sodium carbonate. Dry the organic phase with sodium sulfate and evaporated to dryness, obtaining 17.9 g (100% of 5-benzyloxy-2-methylsulfonylamino.

Data spectroscopy: infrared spectrum IR(Kbr): 1125: 1300 cm-1.

Nuclear magnetic resonance NMR1H ( , , CDCl3): 8,58 (s, 2H); 7,41 (and. C., 5H); at 5.27 (s, 2H); 3,30 (s, 3H).

Compound VI. Obtain 5-benzyloxy-2-piperidinylidene.

Provide reflux for 3 hours the solution 26,36 g (99,8 mmol) and 85 g (99,8 mmol) piperazine in 185 ml of toluene. Leave to cool, filtered and concentrated. From the solution crystallized 19,84 g (73%) of 5-benzyloxy-2-piperidinylidene. Recrystallized from hexane, the product has a melting point 86-91oC.

Data spectroscopy: IR (KBr): 1267, 144 cm-1.

NMR1H ( , , CDCl3): 8,11 (s, 2H); of 7.36.S., 5H); 5,00 (s, 2H); to 3.67 (t, 4H); 2,90 (t, 4H).

Compound VII. Obtain methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere[4,5]decane.

Provide reflux for 8 hours of a solution of 7.25 g (26,85 mmol) 5-benzyloxy-2-piperidinylidene and 3.2 ml (26,85 mmol) of 1,4-dibromobutane in 240 ml of the tilov ether, obtain 16.0 g (91%) of methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere[4,5]decane with a melting point 128-133oC.

Data spectroscopy: IR (KBr): 1268, 1451 cm-1.

NMR1H ( , CDCl3)): 8,13 (s, 2H); 7,38 (and.S., 5H); to 5.03 (s, 2H); 4,01 (and.S., 8H); of 3.77 (t, 4H); to 2.35 (t, 4H).

Compound VIII. Getting 2-{4-[4-(azole-1-yl)-butyl]-1-piperazinil]-5-benzyloxypyridine.

Reaction of methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere[4,5]decane of the formula VII with an azole of the General formula IX

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in which

X2represents a nitrogen atom or a group C-R2X4represents a nitrogen atom or a group C-R4X5represents a nitrogen atom or a group C-R5and R2, R3, R4and R5identical or different, represent a hydrogen atom, halogen, a radical is a lower alkyl, a nitro radical, a hydroxy radical, an alkoxy radical, a cyano radical, a carboxyl radical, carboxamide radical, the radical of alkylcarboxylic, the aryl radical, the radical sulfonamida, radical amino or substituted amino, get the connection with the General formula VIII, in which X2X4X5, R2, R3, R4and R5have the above values. The reaction is carried out in a solvent is s I. Getting 2-{4-[4-azole-1-yl)butyl]-1-piperazinil}-5-hydroxypyrimidine.

Catalytic hydrogenation of compounds of General formula VIII get the connection with the General formula I. In the two compounds X2X4X5, R2, R3, R4and R5have the above values. The reaction is carried out in a solvent such as an alcohol, at temperatures between 15 and 60oC, at pressures between 1 and 15 atmospheres.

In the following examples shows how to obtain the new derivatives according to the invention. The examples presented below, the data just as an illustration, should not however in any way to limit the scope of the invention.

Example 1. Getting 2-{4-[4-(4-chloro-pyrazole-1-yl)butyl]-1-piperazinil} -5-hydroxypyrimidine.

Incubated for 12 hours at phlegm and filtered while hot, the mixture of 12,55 g (30,94 mmol) of methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere[4,5] decane, 3,48 g (34,03 mmol) of 4-chloropyrazole and 8,54 g (61,89 mmol) of potassium carbonate in 250 ml of dimethylformamide. Dimethylformamide is evaporated and chromatographic silica gel, get 6,82 g(51,6%) 2-{4-[4-(4-chloropyrazole-1-yl)butyl]-1-piperazinil}-5-benzyloxypyridine.

Data spectroscopy: IR (KBr): 1256, 1270, 1363, 144, H); to 3.73 (m, 4H); 2,48 (m, 4H); of 2.38 (t, 2H); 1,89 (Quint., 2H); of 1.52 (Quint., 2H).

Stirred for 12 hours in an atmosphere of hydrogen at room temperature (24oC) and at a pressure of 2 atmospheres a mixture of 6,87 g (mmol 16,07) 2-{4-[4-(4-chloropyrazole-1-yl)-butyl]-1-piperazinil}- 5-benzyloxypyridine and 0.63 g of 10% palladium on coal in 160 ml of ethanol. After filtration, washing with ethanol and evaporating to dryness chromatographic with silica gel and obtain 2.65 g(49%) 2-{4-[4-(4-chloropyrazole-1-yl)butyl]-1-piperazinil}-5-hydroxypyrimidine with a melting point 131-132oC.

Data spectroscopy: IR (KBr): 1258, 1271, 1364, 1428 cm-1.

NMR1H ( , CDCl3): to 7.99 (s, 2H); 7,40 (s, 1H); of 7.36 (s, 1H); 4,06 (t, 2H); 3,66 (t, 4H); 2,49 (t, 4H); is 2.37 (t, 2H); of 1.84 (Quint., 2H); for 1.49 (Quint., 2H).

Example 2.

Getting 2-{ 4-[4-(4,5-dichloro-2-Mei-1-yl)butyl]- 1-piperazinil}-5-hydroxypyrimidine.

Incubated for 12 hours at phlegm and filtered while hot, the mixture of 3,59 g (cent to 8.85 mmol) of methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere[4,5] decane, 1.47 g (9.73 mmol) of 4,5-dichloro-2-methylimidazole and 4,89 g (35,41 mmol) of potassium carbonate in 72 ml of dimethylformamide. Dimethylformamide is evaporated and chromatographic silica gel, get 2,90 g(69%) 2-{4-[4-(4,5-dichloro-2-met, 1412, 1580 cm-1.

NMR1H ( , CDCl3): 8,11 (s, 2H); 7,37 (and.S., 5H); free 5.01 (s, 2H); of 3.80 (t, 2H); and 3.72 (m, 4H); 2,48 (m, 4H); a 2.36 (t, 2H); of 2.36 (s, 3H); of 1.65 (m, 4H).

Stirred for 12 hours in an atmosphere of hydrogen at room temperature (24oC) and at a pressure of 0.28 MPa mixture of 2,90 g (6,10 mmol) 2-{ 4-[4-(4,5-dichloro-2-Mei-1-yl)butyl - 1-piperazinil} -5-benzyloxypyridine and 0.30 g of 10% palladium on coal in 50 ml of methanol. After filtration, washing with methanol and evaporation to dryness chromatographic with silica gel and obtain 1.39 g(59%) 2-{4-[4-(4,5-dichloro-2-Mei-1-yl)butyl]-1-piperazinil}- 5-hydroxypyrimidine with a melting point 154-6oC.

Data spectroscopy: IR (KBr): 1250, 1277, 1355, 1408, 1429, 1445, 1469 cm-1.

NMR1H ( , CDCl3): 8,00 (s, 2H); of 3.84 (t, 2H); the 3.65 (m, 4H); 2,49 (m, 4H); 2,39 (t, 2H); 2,32 (s, 3H); 1.69 in (Quint., 2H); of 1.55 (Quint., 2H).

As a result of processing 0.52 g (1,36 mmol) obtained above product dissolved in 15 ml of ethanol, 37% hydrochloric acid get 0,43 (75%) of monochlorohydrin 2-{4-[4-(4,5-dichloro-2-Mei - 1-yl)butyl]-1-piperazinil}-5-hydroxypyrimidine with a melting point 212-6oC.

Data spectroscopy: IR (KBr): 1244, 1269, 1363, 1441, 1474 cm-1.

NMR1H ( , CDCl3): 11,21 (a, 1H); 9,63 (s, 1H); yavlyayut biological activity with the mouse in the experience in light/dark chamber, described B. Costall, etc., J. Pharmacology and Experimental Therapeutics, 1992, 262, 90. The experience is carried out, as described in said publication. More similar method can also be viewed B. Costall and others , Pharmacol. Biochem. Behav., 1989, 32, 777. Connection appoint intraperitoneally and note the results in the form of the minimum dose at which to observe the activity.

Connection - the Minimum dose

Diazepam - 0,125

Ipsapirone - 0,5

Buspiron - 0,125

Lesopitron (E-4424) is 0.0001 - 0,000001

Example 1. Given their strong pharmacological action, the new compounds according to the invention can be used in the treatment of humans and animals, in particular, in the treatment of disorders of the Central nervous system and especially for the treatment of anxiety or sedatives.

In the treatment of a person prescribed dose depends, of course, on the severity of the disease. It may be between approximately 2 and 20 mg / day. Connection objects of the invention, can be produced in the form of tablets, capsules, solutions or suspensions. Below shows as an example two herbal forms of the compounds according to the invention.

3. An example of a composition for tablets.

The compound of example 1 5 mg

Lactose 60 mg

Microk the Colloidal silicon dioxide is 1 mg

Magnesium stearate 1 mg

Weight tablets 100 mg

4. An example of a composition for capsules.

The compound of example 1 10 mg

Polyoxyethyleneglycol - 135 mg

Beginat glycerol, 5 mg

Excipient: gelatin 150 mg

Toxicity was studied on the example of 2-{4-(4-azole-1-yl)butyl-1-piperazinil} -5-hydroxypyrimidine.

Lethal dose affecting 50% of the animals, is for mouse 712 mg/kg orally, 215 mg/kg intraperitoneal; for rats 385 mg/kg orally, 126 mg/kg intraperitoneally.

Thus, the described compounds can be classified as slightly toxic.

1 1. Derivatives of 2-[4(4-azolylmethyl)-1-piperazinil]-pyrimidine of the General formula I 6 1 where X2- CR2and R2is hydrogen or halogen; 4 X4the nitrogen atom or CR4where R4is a hydrogen atom; 4 X5is a nitrogen atom or CR5where R5is lower alkyl; 4 R3- halogen, 1 or their physiologically acceptable salts. 2 2. Compounds of General formula I on p. 1, which are: 2 2-{4-[4-chloropyrazole-1-yl)-butyl]-1-piperazinil}-5-hydroxypyrimidine, 2 2-{4-[4-(4,5-dichloro-2-Mei-1-yl)butyl]-1-piperazinil} -5-hydroxypyrimidine, 2 hydrochloride 2-{4-[4-(4,5-dichloro-2-Mei-1-yl)butyl] -1 -, what does the oxidation of 5-benzyloxy-2-dimethylpyrimidine to obtain the corresponding sulfone of formula V 6 1 carry out the substitution reaction of the radical methylsulfonyl piperazine to obtain the compounds of formula VI 6 1 which is subjected to interaction with dibromobutane to obtain the corresponding Spiro derivative of the formula VII 6 1 carry out the reaction of methyl 8-(5-benzyloxy-2-pyrimidinyl)-8-Aza-5-Sonisphere[4,5] Dean with an azole of the General formula IX 6 1 where X2X4X5, R2, R3, R4and R5are specified in paragraph 1 values, 1 to obtain compounds of General formula VIII 6 1 where X2X4X5, R2, R3, R4and R5have these values, 1 remove the protection from the compounds of General formula VIII by hydrogenation of the benzyl group, with the formation of compounds of General formula I, in which X2X4X5, R2, R3, R4and R5have the specified values. 2 4. Pharmaceutical composition having anxiolytic and calming activity, characterized in that it contains a pharmaceutically acceptable carrier and at least one compound of General formula I or one of its physiologically acceptable sole

 

Same patents:

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -C–ěNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new biologically active chemical compounds, derived pyrazine formula I listed in the description, which is obtained by the interaction of the previously obtained through collaboration pyrazinamide with Amida sodium in liquid ammonia Na-salt pyrazin-2-carboxamide and 6-methyl-5-uracil sulfochloride in liquid ammonia

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

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where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or the same As the ode;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

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ALK is a lower alkyl

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

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aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

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where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

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in which R and m have the above meanings;

Y - group

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where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to new pyridinesulfonamide General formula I or their acceptable for agriculture salts, have a weed-killing activity, as well as to a method for their production and compositions for combating the growth of unwanted vegetation

The invention relates to new derivatives of arylsulfonamides, namely, potassium salt of N-(4,6-dimethylpyrimidin-2-yl)-N'-/2- (methoxycarbonyl)phenylsulfonyl/urea (potassium salt of sulfometuron-methyl), which may find application in forestry planting cedar (Siberian pine, Korean) and non-agricultural land use as a herbicide

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The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinin
The invention relates to a method of allocation of 2-alkyl-4-amino-5-alkoxystyrene (aminopyrimidine), which is an intermediate in the synthesis of vitamin b1and other biologically active compounds, and may find application in the medical industry

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