Method for preparing 3-(2-chloro-5-thiazolylmethyl)-5-methyl-4-nitroiminotetrahydro-1,3,5-oxadi azine

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

 

The present invention relates to a new type of way to obtain substituted 2-nitroguanidine and nitroenamine derivatives.

It is known that to obtain substituted nitroguanidine, nitroenamine and cyanoaniline in these compounds can be introduced additional Deputy (e.g. alkylation), which can be substituted one or more times (see, for example, EP 0375907). The substances used as starting material for carrying out these reactions, several hydrogen atoms, previously proposed substitution reactions of this type are often non-selective, and the process leads to the formation of products with undesirable substituents. As an example, in the above-mentioned EP application describes the obtaining of 1,3-disubstituted 2-nitroguanidine reaction of monosubstituted microestimation with primary amines with simultaneous removal of mercaptan.

However, these containing leaving ancilliary nitrosodimethylamine compounds that are proposed for use in the known methods as starting compounds can be obtained only with the problems of a technological nature. In EP A-0483062 also described is a method of obtaining compounds of the following formula (I) by hydrolysis hexahydrotriazine.

It was found that the above-mentioned methods is Holocene compounds of formula (I) do not satisfy the requirements presented to the chemical method of obtaining such as availability, toxicity, storage stability and purity of the original and auxiliary excipients, time of interaction, the energy consumption and volumes of material that have to deal with during the process, the number and remove accumulation of by-products and waste, as well as the purity and yield of the final product. Therefore, there is a need to develop improved methods of obtaining these compounds.

Thus, the aim of the present invention to provide an improved method of producing substituted 2-nitroguanidine, 2-nitroaniline, 2-cyanoaniline and 2-cyanoimino from easily obtainable starting compounds, which enables specific substitution without the formation of large quantities of undesirable by-products.

Therefore, an object of the present invention is a method of obtaining compounds of the formula

in which

R1denotes a hydrogen atom or a C1-C4alkyl;

R2denotes a hydrogen atom, a C1-C8alkyl, C3-Cbcycloalkyl or a radical-N(R3R4; or R1and R6together represent-CH2-CH2S, because h is th ethylene group linked to the nitrogen atom;

R3and R4each independently of one another denotes a hydrogen atom, a C1-C4alkyl, C3-C6cycloalkyl or the radical-CH2In;

R6denotes a hydrogen atom, a C1-C8alkyl, aryl or benzyl;

or R3and R6together represent-CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-CH2-, -CH2-S-CH2- or-CH2-N(R5)-CH2-;

X denotes N-CN, CH CN, CH-NO2or N-NO2;

And denotes an aromatic or non-aromatic, monocyclic or bicyclic heterocyclic radical which is not substituted or - depending on the capabilities of the replacement ring system from mono to pentosanase substituents selected from the series comprising halogen atoms, C1-C3alkyl, C1-C3alkoxy, halo, - C1-C3alkyl, C1-C3haloalkoxy, cyclopropyl, galactolipid,2-C3alkenyl,1-C3quinil,2-C3haloalkyl and C2-C3haloalkyl, C1-C3alkylthio, C1-C3haloalkylthio, allyloxy, propargyloxy, allylthio, propargite, haloalkoxy, haloalkylthio, cyano and nitro; and

In denotes phenyl, 3-pyridyl or thiazolyl, which is optionally substituted, including from one to three Deputy is out of range, including C1-C3alkyl, C1-C3haloalkyl, cyclopropyl, galactolipid, C2-C3alkenyl, C2-C3quinil, C1-C3alkoxy, C2-C3haloalkyl, C2-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3haloalkylthio, allyloxy, propargyloxy, allylthio, propargite, haloalkoxy, haloalkylthio, halogen atoms, cyano and nitro; wherein conducting the reaction of the compounds of formula

which is known or can be obtained by known methods, where R2, R6and X have the same meanings as those indicated above for formula (I), in the presence of a phase transfer catalyst and a base with the compound of the formula

which is known or can be obtained by known methods, where a and R1have the same meanings as those indicated above for formula (I), and Q denotes a leaving group.

The compounds of formula (I) can partially be in the form of tautomers. Therefore, any reference to compounds of formula (I)above, and further, in all cases should be understood as covering also their corresponding tautomers, even if these latter are not specifically mentioned.

The compounds of formula (I) and, when the reception is emo, their E/Z isomers and tautomers can exist in the form of salts. The compounds of formula (I)which have at least one basic centre are capable of forming, for example, an acid additive salt. They are formed, for example, with strong inorganic acids such as mineral acids, particularly sulfuric acid, phosphoric acid and malovodiane acid, with strong organic carboxylic acids, such as C1-C4alcancarao acid, substituted, for example, where appropriate, by halogen atoms, in particular acetic acid, such as optionally unsaturated dicarboxylic acids, for example oxalic, malonic, maleic, fumaric and phthalic acid, such as hydroxycarbonate acids, for example ascorbic, lactic, malic, tartaric and citric acid, or benzoic acid, or with organic sulfonic acids, such as C1-C4alkanesulfonyl or arylsulfonate acid, substituted, for example, where appropriate, by halogen atoms, for example methanesulfonate or p-toluensulfonate acid. In a preferred embodiment, the salts of the compounds of formula (I) with acids mentioned type get when treated with the reaction mixture.

In a broader sense salts with bases can form compounds of formula (I)containing at least the bottom of the acid group. Acceptable salts with bases are, for example, metal salts such as salts of alkaline and alkaline-earth metals such as sodium, potassium and magnesium salts, or ammonium salts or organic amines, such as morpholine, piperidine, pyrrolidine, mono-, di -, or three(the lowest acylamino), respectively, three(ness.)alkylamine, for example ethyl-, diethyl-, triethyl - or dimethylpropylene, and mono-, di - or rigid-Roxie(ness.)alkylamine, for example mono-, di - and triethanolamine. When this is acceptable, can be also obtained corresponding internal salts. Preferred compounds covered by the scope of the present invention are salts suitable for use in agriculture. In the above part of the present description and in the future under the free compounds of formula (I) you should also understand when it is acceptable analogues of the corresponding salts, and salts should be understood also available compounds of formula (I). The same applies to E/Z isomers and tautomers of compounds of formula (I) and their salts. Free form is preferred.

In the above descriptions of the formulas (I) to (III) and further on the individual symbols you must be aware of the following.

Under the atoms of halogen is meant fluorine atoms, chlorine, bromine and iodine, of which preferred Automator, chlorine and bromine, especially chlorine. In this context, the halogen atom means an independent Deputy or part of a substituent, such as haloalkyl, haloalkylthio, haloalkoxy, halachically, haloalkyl, haloalkyl, haloalkoxy or haloalkylthio. Alkyl, alkylthio-, alkanniny, alkynylaryl and alkoxy radicals can be remotemachine or branched. In all cases, unless otherwise stated, each of the alkyl groups contains up to 6 carbon atoms. Examples of such Akilov which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Alkoxyalkane are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, as well as their isomers. Alkylthio represents, for example, methylthio, ethylthio, isopropylthio, propylthio or the isomeric butylthio. Alkyl, alkoxy, Alchemilla, Alchemilla and cycloalkyl groups, which are substituted by halogen atoms, can be only partially or perhalocarbon. The above definition this description applies to atoms of halogen, alnilam and alkoxy. Examples of the alkyl components of these groups are methyl, from mono - to triamese fluorine atom, chlorine and/or bromine, in particular CHF2or CF3; ethyl which is mono - to pentosanase fluorine atom, chlorine and/or B. the Ohm, in particular CH2CF3, CF2CF3, CF2CCl3, CF2CHCl2, CF2CHF2, CF2CFCl2, CF2CHBr2, CF2CHClF, CF2CHBrF or CClFCHClF; propyl or isopropyl, from mono - to getsemani fluorine atom, chlorine and/or bromine, in particular CH2CHBrCH2Br, CF2CHFCF3CH2CF2CF3or CH(CF3)2; butyl or one of its isomers, mono - to nonsaline fluorine atom, chlorine and/or bromine, in particular CF(CF3)CHFCF3or CH2(CF2)2CF3; 2-chlorocyclopropane or 2,2-divorcecare, 2,2-defermined, 2,2-dichlorovinyl, 2-chlorallyl, 2,3-dichlorovinyl or 2,3-dibromovinyl.

Typical representatives alkenyl and etkinlik groups are allyl, methallyl, propargyl, vinyl and ethinyl. In a preferred embodiment, a double or triple bond in allyloxy, propargyloxy, allylthio, propargite separated from the point of attachment to the heteroatom (N, O or S) saturated carbon atom.

If the described alkyl, CNS, alkeline, alkyline or cycloalkyl group substituted by other substituents, they can be substituted one or more times with substituents similar to the above or different from them. In a preferred embodiment, in the substituted groups should contain one or two additional the of". Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "aryl" denotes phenyl, naphthyl, phenanthrene or anthracene, preferably phenyl. In the context of describing the present invention in a preferred embodiment, the term "heteroaryl radical" is used to denote a 5 - to 7-membered aromatic or not aromatic ring containing one to three heteroatoms selected from the group comprising N, O and S. Preferred aromatic 5 - and 6-membered rings, which include as a heteroatom a nitrogen atom and optionally one additional heteroatom, preferably nitrogen, oxygen or sulfur, mainly nitrogen.

Under the leaving groups Q in the previous part of the present description and in the future understand all the deleted group, in which chemical reactions are conventional and known to the person skilled in the technical field, in particular halogen atoms such as fluorine atoms, chlorine, bromine and iodine, -O-C(=O) -,- O-P(=O)(W)2, -O-Si(C1-C8alkyl), -O-(C1-C8alkyl), -O-aryl, -O-S(=O)2W, -S,-P(=O)(W)2, -S,-P(=S)(W)2, -S-S-(C1-C8alkyl), -S-aryl, -S-(C1-C8alkyl), -S-aryl, -S(=O)W or-S(=O)2W, where the moiety W is optionally substituted C1-C8the alkyl, C2-C8alkenyl,2-C8the quinil, neoba is consequently substituted by aryl, optionally substituted benzyl, C1-C8alkoxy or di(C1-C8alkyl)amine where alkyl groups from each other are independent, NO3, NO2or the rest of sulfate, sulfite, phosphate, phosphite, carboxylate, complex aminoether, N2or the rest of the carbamate. As leaving groups are particularly preferred chlorine atoms and bromine, especially chlorine.

As preferable compounds in the implementation of the method proposed in accordance with the invention, are compounds of formula (I),

in which R1denotes a hydrogen atom;

in which R2refers to the radical-N(R3R4;

in which R3denotes a hydrogen atom or a C1-C4alkyl;

in which R4denotes a hydrogen atom;

in which R2refers to the radical-N(R3R4and R3and R6together represent-CH2-CH2-, -CH2-O-CH2- or-CH2-N(CH3)-CH2-mainly-CH2-CH2- or-CH2-O-CH2-;

in which R6denotes a hydrogen atom, a C1-C8alkyl, aryl or benzyl;

in which X denotes CH-NO2or N-NO2mainly N-NO2;

in which a denotes pyridyl, thiazolyl or tetrahydrofuranyl, optionally substituted atom ha is ogena, C1-C3the alkyl, C1-C3alkoxy, halo,-C1-C3the alkyl, C1-C3haloalkoxy, mostly 2-chlorothiazole-5-yl or 2-chloropyrid-5-yl.

In the most preferred embodiment of the method in accordance with the invention have the following individual compounds:

(instead of dots to place the formulae given on pages 6 and 7 of the original)

thiamethoxam formula

known from EP-580553;

Imidacloprid formula

known from The Pesticide Manual, edition 11-E. (1997), The British Crop Protection Council, London, S. 706;

acetamiprid (NI-25) formula

known from The Pesticide Manual, edition 11-E. (1997), The British Crop Protection Council, London, p.9;

nitenpyram (TI-304) formula

known from The Pesticide Manual, edition 11-E. (1997), The British Crop Protection Council, London, s;

clothianidin (Ti-435) formula

known from EP-0375907;

MTI-446 formula

known from EP-0649845;

thiacloprid formula

known from EP-192060, and

the compound of the formula

known from EP-0428941.

As all of interphase catalysts can be applied ordinary connected to the I, i.e. salts of Quaternary ammonium salts of Quaternary phosphonium, crown-ethers, chelating agents, 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), their Quaternary ammonium salts, and polymer interphase catalysts. The list is given in the scientific report "Phase Transfer Catalysts prepared by the company Fluka, Buchs, Switzerland, edition 1986, S. from 7 to 25. Thus, listed in this work, interfacial catalysts included in the description of the present invention as references.

Particularly preferred Quaternary ammonium salts as phase-to-phase catalysts are, for example, benzyltrimethylammonium, benzyltriethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltrimethylammonium, benzyltriethylammonium (Triton), glycidylmethacrylate, hexadecyltrimethylammonium, hexadecyltrimethylammonium, hexadecylpyridinium, hexadecylpyridinium, 2-hydroxyethylmethacrylate, 2-hydroxyethylmethylcellulose, phenyltrimethylammonium, phenyltrimethylammonium, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium, tetrabutylammonium, tetradecylammonium, tetradecylammonium, tetraethylene ichorid, tetraethylorthosilicate, tetradecylammonium, tetradecylthioacetic, tetradecylammonium, tetradecylammonium, Tetramethylammonium, tetraethylammonium, Tetramethylammonium, tetraethylammonium, tetrabutylammoniumsulphate, tetraoctylammonium, tetrapropylammonium, tetrapropylammonium, tributyltinhydride and tributylammonium, with the most preferred Quaternary ammonium hydroxides, in particular Tetramethylammonium in pentahydrate form.

Salts of Quaternary phosphonium can be benzyltriphenylphosphonium, hexadecyltrimethylammonium, hexadecyltrimethylammonium, tetrabutylphosphonium, tetraphenylphosphonium and tetraphenylphosphonium and hexyltrimethoxysilane enshrined in the polymer matrix.

Crown ethers as phase-to-phase catalysts in the synthesis method in accordance with the invention can be, for example, 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6; glycols, for example, the average molecular weight of 1000, 1500 or 2000; tetraethylene glycol and tetraethylethylenediamine ether.

Preferred for implementing the method in accordance with the invention, the solvents or diluents are complex EPE is s, such as ethyl acetate; ethers, such as diethyl ether, DIPROPYLENE ether, diisopropyl ether, disutility ether, tert-butyl methyl ether, etilenglikolevye ether, etilenglikolevye ether, etilenglikolevye ether, dimethoxyethane ether, tetrahydrofuran and dioxane; ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; amides such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-organic and triamide hexamethylphosphoric acid; NITRILES such as acetonitrile and propionitrile; and sulfoxidov, such as dimethyl sulfoxide; and water.

Particularly preferred esters of coal acid, acetic acid, formic acid, ketones, NITRILES, ethers, amides, N-alkyl acids, dimethylsulfoxide, N-alkylpyridine, mainly acetonitrile, dimethylcarbonate, diethylcarbamyl, N-organic, dimethylformamide, dimethylacetamide, ethoxyethylacetate, methyl acetate, propionitrile, butyronitrile, dimethylsulfoxide, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone.

Especially preferred solvents are acetonitrile, dimethylcarbonate, diethylcarbamyl, N-organic, dimethylformamide, dimethylacetamide and ethoxyethylacetate, especially dimethylcarbonate.

Especially preferred is a combination of DIMET carbonate as solvent and Tetramethylammonium as phase transfer catalyst.

Bases in anhydrous systems can serve, in particular, carbonates, and water solvent system use also add to the regulation of the pH of the hydroxides of alkali metals; the preferred potassium carbonate. In a preferred embodiment, the amount of base is from one to two moles per mole of the compounds of formula (III).

The reaction conditions depend on the boiling point of the employed solvent. Suitable temperature range is from about 40 to about 100°C, preferably in the range from about 60 to about 70°C.

The preferred reaction time is from about 0.1 to about 24 hours, mostly from about 3 to about 5 hours

It was found that the implementation of the method in accordance with the invention enables substantially to meet at the beginning of the present description requirements, particularly those related to the purity of the material.

Thus, in particular, it was demonstrated that, when implementing the method in accordance with the invention may suppress formation of undesirable isomers. In particular, in the case guanidino derivatives was shown that the substitution may also occur on the nitrogen atom that bears a nitro - or cyano groups is,

for example,

The use of suitable phase transfer catalysts allows the use of solvents that generate only small amounts of undesired isomers and which can be easily regenerated.

Examples retrieve

P1: obtain 5-(2-chlorothiazole-5-ylmethyl)-3-methyl-4-micromanipulator-1,3,5-oxadiazine (thiamethoxam)

184 g of 100%3-methyl-4-micromanipulator-1,3,5-oxadiazine 400 g dimethylcarbonate load in a sulphonation flask and melt add 168 g of 100%2-chloro-5-chloromethylthiazole (1,0 mol). This mixture is heated to 65°C. With simultaneous stirring for 60 minutes at a temperature of from 62 to 68°To dispense a mixture containing 350 g of dimethylcarbonate, 4 g of the pentahydrate of tetramethyldisiloxane and 242 g of powdered potassium carbonate.

With simultaneous vigorous stirring, the reaction mixture was incubated for 5 to 6 h, prior to the entry into interaction more than 99% of 2-chloro-5-chloromethylthiazole (control liquid chromatography).

Subsequently the reaction mixture is cooled to a temperature of from 45 to 50°and mixed with 600 g of water. The addition of approximately 260 g of 32%hydrochloric acid, the pH of the reaction mixture was adjusted to 6.5, and then maintained at a temperature which e from 60 to 65° C until complete dissolution. The solution is allowed to stand until phase separation and separate the organic phase. At 50°the aqueous phase is re-extracted with 300 g of dimethylcarbonate.

The organic phase in the re-extraction combined with the organic phase from the reaction mixture. The combined organic phases are concentrated under vacuum (pressure of from 350 to 400 mbar) at a temperature of from 60 to 65°to the final weight 600 g (480 ml). The mixture is slowly cooled to a temperature of from 0 to 5°and incubated for 1 h Then, the resulting suspension filtered.

The filter cake is washed at a temperature of from 5 to 10°With 300 g of dimethylcarbonate in two portions, and then 300 ml of water in two portions and the wet product is dried under vacuum at 70°C.

Output: from 218 to 220 g specified in the title of the product purity of 98 to 99% (74% of theoretical based on 100%of 2-chloro-5-chloromethylthiazole). The above isomer of formula (IV) not found.

By recrystallization from dimethylcarbonate specified in the title of the product can be obtained with a purity of 99.5%.

Another way of obtaining includes the simultaneous addition of potassium carbonate, 3-methyl-4-micromanipulator-1,3,5-oxadiazine and pentahydrate of tetramethyldisiloxane in 1100 g of dimethylcarbonate and dosing at 65°C for 60 min, 2-chloro-5-hormati is thiazole. Further subsequent reaction and the treatment is carried out similarly to the above.

The method of obtaining the compounds of formula

characterized in that the compound of the formula

subjected to interaction with the compound of the formula

where Q denotes a chlorine or bromine in the presence of a solvent or diluent, interphase catalyst and substrate, and the solvent or diluent represent an ester of carbonic acid, interfacial catalyst is a Quaternary ammonium salt, and the base is a carbonate.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to compounds with dual biological activity, the method of their preparation and to pharmaceutical compositions based on them

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - arylamidrazone derivatives of formula ,

where R1 is a C2-C8 alkyl group or a C2-C8 alkoxy group, which can be substituted with a halogen or a C1-C8 alkoxy group; a 5-7-member aromatic heterocycle containing 1 or 2 oxygen, nitrogen or sulphur atoms, or phenyl, which can be substituted with a halogen, a C1-C8 alkyl group, a haloC1-C8alkyl group or a C1-C8alkoxy group; or NR4R5; R2 and R3 are identical or different, and each is a hydrogen atom, a halogen atom, a halogenC1-C8alkyl group, a C1-C8alkyl group, a C2-C6alkynyl group, a C1-C8alkoxy group, a cyano group, a C2-C6alkanoyl group or a C1-C8alkylsulphonyl group; A is a benzene, pyridine, quinoline or isoquinoline ring; D is a single bond or methylene; m assumes values from 1 to 3 and n assumes values from 1 to 5, having antagonistic effect on S1P3 receptors, as well as to medicinal agents and pharmaceutical compositions containing such compounds as an active ingredient.

EFFECT: improved properties.

13 cl, 161 ex, 19 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - N'-(1-methylethylidene)heptadecafluorooctyl carboxamidrazone of formula which can be used as material of a standard sample of a composition for quantitative determination of fluorine in organic compounds using a spectrophotometric method. The invention relates to a method of producing N'-(1-methylethylidene)heptadecafluorooctyl carboxamidrazone of formula (1) and an intermediate compound, heptadecafluorooctyl carboxamidrazone of formula used in synthesis thereof.

EFFECT: high efficiency of using the compound.

3 cl, 2 tbl, 1 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

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