Method for preparing benzenesulfonyls

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of aromatic sulfonyl halides by interaction of substituted phenolic compound with halogensulfonic acid and trifluoroacetic acid. Also, invention involves a method for synthesis of 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide of the formula (1) that is useful in treatment of disorders associated with cyclooxygenase-2 and involves interaction of a precursor-compound chosen from group consisting of compounds of the formula (2) and formula (3) with halogensulfonic acid in the presence of trifluoroacetic acid to yield a halogensulfonated compound, and interaction of a halogensulfonated compound with ammonium source to yield compound (isoxazol-4-yl)-benzenesulfonamide of the structural formula (1).

EFFECT: improved method of synthesis.

147 cl, 7 ex

 

The present invention relates to a method for producing aromatic sulphonylchloride and isoxazolecarboxylic. This way, in particular, relates to a method of obtaining valdecoxib, parecoxib, parecoxib sodium 4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide.

Substituted isoxazolidine compounds useful in the treatment of inflammation, as described in U.S. patent No. 5633272. Ways of getting benzosulfimide substituted isoxazol-4-ilen compounds described in U.S. patent No. 5859257. Methods of making prodrugs of COX-2 inhibitors described in U.S. patent No. 5932598. In Ullmann''s Encyclopedia of Industrial chemistry, 5thEdition, Vol. A3 on page 513 retrieves aromatic sulphonylchloride using an excess of chlorosulfonic acid. In Ullmann''s Encyclopedia also describes the extraction of aromatic sulfonamides of the aromatic sulphonylchloride.

When the reaction chlorosulfonylphenyl secondary reactions such as the formation of sulfone and polychloroethene, can be minimized by using a large excess chlorosulfonic acid by dilution with a solvent or by adding substances inhibiting the formation of sulfone as described in U.S. patent No. 5136043. Adding additional gloriously agents, such as thionyl chloride (EP 115328), complicates the way through in which to enter additional operations and complications of manipulation with waste at the same time does not solve problems with reactivity associated with the insolubility of the reagents. The use of chlorinated solvents such as carbon tetrachloride, chloroform or methylene chloride, although partially solves some of the problems associated with solubility, complicates this process due to the formation of two-phase reaction mixture, creates service personnel problems associated with the volatility and toxicity of these solvents, and optionally enters the chlorinated solvents in the waste streams. In the patent application of Japan room JP06-145227 describes the interaction of high density polyethylene (HDPE) with sulfurylchloride in triperoxonane acid in the presence of AIBN (generator radicals) obtaining chlorosulfonylbenzoic polyethylene, which is used in the production of rubber.

Future work in the field of synthesis of aromatic sulfonamides and using compounds of isoxazolecarboxylic in the treatment of inflammation indicates the continuing need for an economical, practical and acceptable for the environment ways of producing these compounds.

The present invention provides a new method for producing aromatic compounds sulphonylchloride, in General, and of the corresponding compounds of isoxazolecarboxylic, compounds N-[[4-(3-f is melisaratos-4-yl)phenyl]sulfonyl]propanamide and sodium salts of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide. Among the several embodiments of the present invention may be noted the creation of a method for obtaining aromatic compounds sulphonylchloride; providing a method for producing compounds [isoxazol-4-yl]benzosulfimide, compounds N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide and sodium salts of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide. In one of the embodiments of the present invention provides a method of obtaining [isoxazol-4-yl]benzosulfimide structural formula1:

where the method involves reacting a compound of precursor selected from the group consisting of compounds of the formula2and the formula3:

with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product; and interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide (valdecoxib) structural formula1.

In another embodiment of the present invention provides a method of obtaining N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide (parecoxib) structural formula1a.

where the method includes the interaction with the unity predecessor selected from the group consisting of compounds of the formula2and the formula3with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product; interaction halogencontaining product with a source of ammonium obtaining [isoxazol-4-yl]benzosulfimide; and interaction sulfonamida with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1a.

In another embodiment of the present invention provides a method of obtaining a sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide (parecoxib sodium) structural formula1b

where the method involves reacting a compound of precursor selected from the group consisting of compounds of the formula2and the formula3with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product; interaction halogencontaining product with a source of ammonium obtaining [isoxazol-4-yl]benzosulfimide; interaction sulfonamida with propionyloxy agent with obtaining N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; and the interaction of propanamide sodium ground floor with the rising of sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1b.

In another embodiment of the present invention provides a method of obtaining N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]sulfonamida structural formula1where the method includes the formation of a derivative diphenylethanone by reacting 1,2-diphenylethanone source hydroxylamine; the interaction of a particular derived oxime with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene; interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product; and interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1.

In another embodiment of the present invention provides a method of obtaining N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide formula1awhere the method includes the formation of a derivative diphenylethanone by reacting 1,2-diphenylethanone source hydroxylamine; the interaction of a particular derived oxime with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene; interaction derived diphenylacetone with triperoxonane acid and halog Sultonova acid with the formation of halogencontaining product; interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1; and the interaction of compounds sulfonamida with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1a.

In another embodiment of the present invention provides a method of obtaining a sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1bthat includes the formation of a derivative diphenylethanone by reacting 1,2-diphenylethanone source hydroxylamine; the interaction of a particular derived oxime with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene; interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product; interaction halogencontaining product with a source of ammonium obtaining [isoxazol-4-yl]benzosulfimide1; interaction sulfonamida with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1a; and the interaction of compounds propanamide sodium is the basis of obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1b.

In another embodiment of the present invention provides a method for obtaining compounds of benzosulphochloride structural formula4:

where X represents a halogen atom and R1, R2, R3, R4and R5independently selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl; where the alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, each optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, halogenosilanes, alkoxyaryl, halogenoalkane and alkoxylalkyl; where the method includes the interaction of substituted phenyl compounds of structural formula5:

with halogencontaining acid in the presence triperoxonane acid with the formation of compounds benzosulphochloride.

In another embodiment of the present invention provides a method of obtaining a 5-phenylisoxazol-4-yl-benzosulphochloride, including the interaction of the compound 4,5-diphenylethanol with halogencontaining acid in the presence triperoxonane to the slots with the formation of the compounds 5-phenylisoxazol-4-yl-benzosulphochloride structural formula 6:

Additional limits of applicability of the present invention will become apparent from the detailed description below. However, it should be understood that the following detailed description and examples, although showing a preferred embodiment of the present invention are given only by way of illustration, since various changes and modifications within the scope of the present invention will be clear to the person skilled in the art from this detailed description.

1demonstrates the way in which can be obtained 4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide structural formula1.

Figure 2 shows the manner in which the compounds of structural formula1aand1bcan be obtained from compounds of structural formula1.

The following further detailed description is provided to assist the specialists in this field in the implementation of the present invention. Even in this case, this detailed description should not be construed as limiting the present invention as modifications and variations of the embodiments discussed herein may be carried out by the person skilled in the art without deviating from the scope of content of the present invention.

The content of each of the references cited here, VK is Ucha the content of the links quoted in these primary links that are included in this description as a reference in their entirety.

a. Definitions

The following definitions are provided for understanding the detailed description of the present invention:

"Alkyl", "alkenyl" and "quinil", unless otherwise specified, are each a hydrocarbon group with a straight chain or branched chain, containing from one to about twenty carbon atoms for alkyl or from two to about twenty carbon atoms for alkenyl and quinil in the present invention, and therefore represent, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethynyl, propenyl, butenyl, pentenyl or hexenyl and ethinyl, PROPYNYL, butynyl, pentenyl or hexenyl, respectively, and their isomers.

"Cycloalkyl" represents a single or multiring carbocycle, where each ring contains from three to ten carbon atoms and where any ring may contain one or more double or triple bonds. Examples include such radicals as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl and cycloheptyl.

"Aryl" denotes fully unsaturated single or multiring carbocycle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl or anthracene.

"Heterocyclyl" refers to saturated and the unsaturated single or multiring carbocycle, where one or more carbon atoms can be replaced by N, S, P, or O. this includes, for example, the following structures:

where Z, Z1, Z2or Z3represents C, S, P, O or N, provided that one of Z, Z1, Z2or Z3is other than carbon, but is not O or S when attached to another atom, Z is a double bond or when attached to another atom, O or S. in Addition, the optional substituents, as is clear, is attached to Z, Z1, Z2or Z3only when each of them is a C. Point attaching molecules of interest can be on the heteroatom or anywhere else within the ring.

The term "alkoxy" means a radical containing an alkyl radical, which is linked to the oxygen atom, such as methoxyacetyl. More preferred alkoxyalkyl constitute the lower alkoxyalkyl having from one to ten carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

The term "alkylamino" denotes a radical containing an alkyl radical, which is linked to the nitrogen atom, such as N-methylaminomethyl. Preferred radicals are lower acylaminoalkyl having from one to ten and carbon atoms. Examples of such radicals include N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N,N-dipropylamino, N-butylamino and N-methyl-N-ethylamino.

The term "alkylthio" denotes a radical containing an alkyl radical, which is linked to the sulfur atom, such as methylthioethyl. More preferred alkylthiomethyl constitute the lower alkylthiomethyl having from one to ten carbon atoms. Examples of such radicals include methylthio, ethylthio, propylthio, butylthio.

The term "acyl" denotes a radical containing an alkyl or aryl radical, which is linked to carboxypropyl, such as carboxymethyl radical. Preferred acyl radicals are carboxylate alkyl radicals having from one to ten carbon atoms, and carboxyaniline radicals. Examples of such radicals include carboxymethyl, carboxyethyl and carboxypropyl.

The term "halogen" refers to a group of fluorine, chlorine, bromine or iodine.

The term "halogenated" refers to alkyl substituted by one or more Halogens. Examples of such radicals include chloromethyl, deformity, trifluoromethyl, pentafluoroethyl, dichloromethyl, trichloromethyl.

When they are used in combination, for example, "galgenlieder", "alkoxyaryl" or "alkoxyalkyl", individual terms, perejil is installed above have the meanings specified above.

In this description, Me denotes methyl; Et means ethyl, Pr means propyl; i-Pr or Prieach represents isopropyl; Bu denotes a butyl; t-Bu or Butevery one represents tert-butyl.

A weak acid is an acid of such strength to get protonated hydroxylamine in an amount sufficient to interact with the connection of diphenylethanone, derivatization connection diphenylethanone.

A strong base is a base that when interacting with the derived connection oxime gives enough dianionic particles for further interaction with azetiliruet agent.

Deprotonate base is a base that communicates with a salt of hydroxylamine with getting hydroxylamine in sufficient quantity for further interaction with the connection of diphenylethanone, derivatization connection diphenylethanone.

Propionyloxy agent refers to an agent that when interacting with the connection benzosulfimide structural formula1network connection sulfanilamide. Propionyloxy agent may include an active ester, such as propionyloxy anhydride, propionyloxy mixed anhydride, propionyloxy tiefer, PR is piercebody or the like. Propionyloxy agent also includes Propionaldehyde, preferably, propionitrile, active amides, such as N-propylimidazol, N-alkyl-N-alkoxyamine and the like. Numerous active propionyloxy agents described in M. Bodanszky,Principles of Peptide Synthesis14-61 (second revised edition, Springer Verlag 1993).

Allerease agent is an agent that, when interacting with the derivedthe reaction of 1,2-diphenylethanone in the presence of a strong base gives the connection isoxazolyl or connection isoxazol structural formula2and/or3. Alleluya agents may include acetic anhydride, preferably dioksyny anhydride. Allerease agent may also include allalone, preferably, acetylchloride. Allerease agent may also include a Cl-about C6alkyl acetate selected from the group consisting of methyl acetate, ethyl acetate, propyl and butyl acetate, and more preferably ethyl acetate.

Sodium base is a base which, in contact with the connection of benzoylpropionic structural formula1agives compound sodium salt of sulfanilamide. Sodium base may include sodium hydroxide, sodium alkoxide, such as ethoxide sodium or sodium methoxide. Sodium base may also provide the identification of a sodium hydride or sodium carbonate.

The protective group is a chemical residue that serves to protect the functional chemical groups in the molecule, at a time when the molecule undergoes a chemical reaction at another site in the molecule. Preferably, after the chemical reaction of the protective group can be removed to make available the original functional chemical group. The hydroxyl-protective group, for example, can protect the hydroxyl group. Protected hydroxymethylene group contains hydroxymethylene group in which a hydroxyl group protected by a protective group. Used protective groups can vary widely in chemistry. Numerous hydroxyl-protective group described in Theodora W. Greene and Peter G.M. WutsProtective Groups in Organic Chemistry86-97 (Third Edition, John Wiley & Sons, 1999). Example protected hydroxymethylene group is deactivated benzyloxyaniline group and the like.

b. Features of the way

In accordance with the present invention provides a method of obtaining derivatives benzosulfimide, in particular, 4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide structural formula6, 4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide (valdecoxib) structural formula1,N-[[4-(5-methyl-4-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide (parecoxib the structural formula 1aand sodium salt of N-[[4-(5-methyl-4-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide (parecoxib sodium) structural formula1b. The diagram of a method of obtaining valdecoxib, according to the present invention, is shown in figure 1. The diagram of a method of obtaining parecoxib and parecoxib sodium from valdecoxib according to the present invention is shown in figure 2.

In one of the embodiments of the present invention provides a method of producing compound [isoxazol-4-yl]benzosulfimide structural formula1including interaction of compounds, precursor selected from the group consisting of compounds of the formula2and the formula3with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product and interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1. Galogenarenov acid suitable for use in various embodiments of the present invention, for example, may be of any convenient halogencontaining acid. Preferably, halogencontaining acid selected from the group consisting of bromsulphalein acid and chlorosulfonic acid, and more preferably chlorosulfonic acid. The source is ammonium, suitable for use in various embodiments of the present invention, for example, may be selected from the group consisting of ammonium hydroxide and anhydrous ammonia. The preferred source of ammonium includes ammonium hydroxide. In another preferred embodiment, the source of ammonium includes anhydrous ammonia.

In another embodiment of the present invention provides a method of obtaining the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1aincluding interaction of compounds, precursor selected from the group consisting of compounds of the formula2and the formula3with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product, interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1and the interaction of the compounds [isoxazol-4-yl]benzosulfimide with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1a. Propionyloxy agent suitable for use in various embodiments of the present invention, for example, may be selected from the group consisting of propionic anhydride sour is s, Propionaldehyde, proponiamo of tiefer, propionylcarnitine and N-propylimidazol. Preferably, propionyloxy agent is an anhydride of propionic acid, more preferably, propionic anhydride, more preferably, Propionaldehyde and even more preferably, propionitrile.

In another embodiment of the present invention provides a method of obtaining a sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1bincluding interaction of compounds, precursor selected from the group consisting of compounds of the formula2and the formula3with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product, interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1the interaction of the compounds [isoxazol-4-yl]benzosulfimide structural formula1with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1aand then the interaction of the compounds of formula1asodium base with obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]prop is named structural formula 1b. Sodium base, suitable for use in various embodiments of the present invention, for example, selected from the group consisting of sodium hydroxide, sodium alkoxide, sodium hydride and sodium carbonate. Preferably, the sodium base is a sodium methoxide and more preferably, the sodium base is a hydroxide of sodium.

In another embodiment of the present invention provides a method of producing compound [isoxazol-4-yl]benzosulfimide structural formula1,including the interaction of the compounds 1,2-diphenylethanone source of hydroxylamine with the formation of derived compounds diphenylethanone, interaction derived compounds reaction with a strong base and azetiliruet agent with obtaining derived diphenylacetone, interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product and interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1.Source hydroxylamine, suitable for use in various embodiments of the present invention, for example, may be an aqueous solution, aderrasi hydroxylamine. Preferably, the source of hydroxylamine is an aqueous solution containing hydroxylamine and a weak acid with a weak acid is a carboxylic acid and, preferably, alkalicarbonate acid, and even more preferably, alkalicarbonate acid selected from the group consisting of formic acid, acetic acid and propionic acid, and more preferably, is an acetic acid. Most preferably, the source of hydroxylamine is an aqueous solution of hydroxylamine and acetic acid.

Source hydroxylamine may also contain a salt of hydroxylamine and deprotonized basis. Salt of hydroxylamine selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate. The salt of the hydroxylamine is preferably hydroxylamine hydrochloride. Deprotonate base selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium acetate. Deprotonate base preferably represents a sodium acetate. Another preferred source contains hydroxylamine, hydroxylamine hydrochloride and sodium acetate.

Strong base, which interacts with the derived oxime compound, suitable for use in razlicnosti of the present invention, for example, there may be preferably selected from the group consisting of Nitidulidae, argillite, arylalkylamine and alkylate. A strong base can be Nitidulidae and preferably sitedisability. More preferably, the strong base is a C1-about C10alkylate and more preferably, is selected from the group consisting of utility, hexalite, satillite, octillery, and even more preferably, utility or exility.

Acetylide agent suitable for use in various embodiments of the present invention, for example, may be selected from the group consisting of alkyl acetate, acetic anhydride, N-alkyl-N-alkoxyacetic and acetylchloride. Azetiliruet agent may be acetic anhydride and preferablyis acetic anhydride and can be acetylsalicinic and preferably acetylchloride, and more preferably, Cl-about C6alkyl acetate selected from the group consisting of methyl acetate, ethyl acetate, propyl and butyl acetate, and more preferably ethyl acetate.

In another embodiment of the present invention provides a method of obtaining the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1athat includes the interaction of the compounds 1,2-given is latanna source of hydroxylamine with the formation of a derivative diphenylethanone; interaction derived compounds reaction with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene; interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product; interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula1; and the interaction of the compounds [isoxazol-4-yl]benzosulfimide with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1a.

In another embodiment of the present invention provides a method of obtaining a sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1bthat includes the formation of a derivative compound diphenylethanone by reacting compounds 1,2-diphenylethanone source hydroxylamine, interaction derived compounds reaction with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene, interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1the interaction of the compounds [isoxazol-4-yl]benzosulfimide with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1aand further interaction of the compounds of the formula1asodium base with obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula1b.

In another embodiment of the present invention provides a method for obtaining compounds of benzosulphochloride structural formula4:

where X represents a halogen atom and R1, R2, R3, R4and R5independently selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl; where the alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, each optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, halogenosilanes, alkoxyaryl, halogenoalkane protected hydroxymethyl, killsometime and alkoxylalkyl; where the method includes the interaction of substituted phenyl compounds of structures the second formula 5:

with halogencontaining acid in the presence triperoxonane acid with the formation of the compounds benzosulphochloride.

The preferred embodiment of the present invention is a method, where R3is heterocyclyl, optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, halogenosilanes, alkoxyaryl, halogenoalkane, alkoxycarbonyl protected hydroxymethyl, killsometime and alkoxylalkyl; and R1, R2, R4and R5represent hydrogen. Even more preferred is a method, where R3selected from the group consisting of isoxazolyl and pyrazolyl, where R3optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, halogenosilanes, alkoxyaryl, halogenoalkane, alkoxycarbonyl protected hydroxymethyl, killsometime and alkoxylalkyl; and R1, R2, R4and R5represent hydrogen.

In another embodiment of nastoyascheevremya provides a method of obtaining a 5-phenylisoxazol-4-albenzaalbenza, where the method involves reacting 4,5-diphenylethanol with halogencontaining acid in the presence triperoxonane acid to obtain the compound 5-phenylisoxazol-4-albenzaalbenza structural formula6:

In another embodiment of the present invention provides a method of obtaining a 5-phenylisoxazol-4-yl-benzosulphochloride, including the interaction of the compounds selected from the group consisting of compounds of the formula2and the formula3with halogencontaining acid in the presence triperoxonane acid with the formation of the compounds 5-phenylisoxazol-4-yl-benzosulphochloride structural formula6.

As provided herein, triperoxonane acid is a suitable solvent for halogensulphonylphenyl aromatic compounds, the corresponding arylsulfonamides. Use triperoxonane acid provides the solubilization of a variety of solid substrates. Higher boiling point triperoxonane acid, compared with methylene chloride makes it possible to carry out reaction of halogensulphonylphenyl at higher temperatures and reduces the periods of duration d is of capabilities. In addition, triperoxonane acid can be used for pre-dissolving solid aromatic substrates, making it more easy and safe transfer of the substrate from the filtration device in the reactor halogensulphonylphenyl. Use triperoxonane acid also eliminates chlorinated hydrocarbons from emissions to air and water flows waste.

The reaction halogensulphonylphenyl, in which connection2,3and5interact with the formation of aromatic sulphonylchloride structural formulas4and6,carried out in the presence of triperoxonane acid.

The ratio of used triperoxonane acid and the reaction time may vary, as shown in the table below.

Equivalents of TFATemperature

°C
The reaction time

Hours (h)
Time

complete
Valdecoxib1
2,0702<30 min78
2,04063.3 hours80
3,060350 min76
4,0702,5 1 hour87
4,04044 hours77
1Final values of mole.%for samples from the process, quenched with a mixture of acetonitrile, water and ammonium hydroxide.

It is preferable to use triperoxonane acid in a quantity sufficient to provide a fluid reaction mass. To convert2and3in6the number triperoxonane acid can vary from about 1.5 to about 4 mass equivalents, relative to the2and3.In one of the preferred embodiments the mass equivalent triperoxonane acid is equal to the mass of the2and3.

The reaction halogensulphonylphenyl can occur in a wide range of temperatures and is preferably in the range from -20°C to 100°C, and more preferably, from about 30°C to 70°C, even more preferably from about 55°C to 65°C. the Reaction chlorosulfonylphenyl can occur at atmospheric pressure or at elevated pressure and preferably at a temperature below the boiling point triperoxonane acid at atmospheric pressure. Chlorsulfuron can occur at higher temperatures, when the pressure in si is theme of the reactor, sufficient to prevent losses associated with volatility.

SEO ways to get

Source materials for use in the methods of manufacturing of the present invention are known or can be obtained by conventional methods known to experts in the field, or analogously to the methods described in this field. The following examples are intended to illustrate many of the embodiments of the present invention and not intended to be limiting thereof.

Generally, the methods of the present invention can be implemented as follows. Getting on a large scale can be carried out, for example, by a proportional increase in the quantities of ingredients.

Example 1

Getting 4-(5-methyl-3-phenyl-4-isoxazolyl)benzosulfimide (valdecoxib,1)

Stage 1:Getting oxime 1,2-diphenylethanone,7

To a solution of deoxybenzoin (2.3 kg, 11.7 mol), acetic acid (669 ml, 11.7 mol) and ethanol 3A (8,05 l, fortress 190) at 70°C through the addition funnel, add 50 weight percent hydroxylamine (800 ml, 13.3 mol). The addition funnel is washed with water (460 ml) and the reaction mixture was kept at 70°C for 1 hour. The degree of completion of the reaction is followed by HPLC. The water load in eactor (2,87 l) and the temperature is reduced to 50° C. an Aliquot (250 ml) is removed from the reactor, cooled and allowed to crystallize. This mixture is re-injected into the reactor for persecution load and to initiate crystallization. The persecution is not necessary, but if used, it helps to increase the bulk density of the product of the reaction, thereby improving associated with the manipulation of the properties of the obtained oxime. After stirring for 1 hour, add water (8,78 l) for 2.5 hours and the mixture is cooled to 20°C. the Mixture is filtered under pressure; and the residue on the filter is washed with a mixture of 2:1 water/ethanol 3A (10,8 l)and then water (4.5 l). The filter cake is dried by blowing N2during the night to obtain white solids (2,34 kg, yield 95%, 96:4 E/Z isomers of oxime). MS high resolution (ES) m/z(M+H)+calculated: 212,1075; found 212,1085.

Stage 1 (alternative method): Getting oxime 1,2-diphenylethanone,7

To a solution of deoxybenzoin (75,0 g, 0,382 mol), sodium acetate (34,5 g, 0,420 mol) and ethanol 3A (267 ml, fortress 190) at 70°Cplunger pump type 35 weight percent of hydroxylamine hydrochloride (72,0 ml, 0,420 mol). The reaction mixture was kept at 70°C for 1 hour and keep track of the degree of completion of the reaction by HPLC. Charged to the reactor water (75,0 ml) and lower the temperature to 50°C. an Aliquot (0.5 ml) is removed from the reaction is ora, cooled and allowed to crystallize. This mixture is re-injected into the reactor for persecution load and to initiate crystallization. The persecution is not necessary, but if used, it helps to increase the bulk density of the product of the reaction, thereby improving associated with the manipulation of the properties of the obtained oxime. After stirring for 1 hour, add water (274 ml) for 1 hour and cooling the mixture to 20°C. the Mixture is filtered; the precipitate on the filter is washed with a mixture of 2:1 water/ethanol 3A (188 ml)and then water (100 ml). The filter cake is dried in a vacuum oven at 50°C for 16 hours to obtain white solids (76,39 g, yield 95%, 97:3 E/Z isomers of oxime).

Stage 2:__Obtaining 4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazolone,2

In a 500 ml reactor equipped with a casing, a mechanical stirrer, thermocouple and inlet for nitrogen at a positive pressure, load 1,2-diphenylethanone (31.4 grams). Add tetrahydrofuran (THF) (160 ml), with stirring, to dissolve the solids. The reaction mixture is cooled using temperature casing -15°C. In the reaction capacity load n-exility in hexane (131 ml, 2,3M), while maintaining the temperature below 10°C. After complete addition, the mixture is stirred for 30 minutes using a temperature casing -15�B0; C. Add ethyl acetate (120 ml), keeping the temperature below 10°C. Then the reaction mixture was transferred via cannula to a mixture of sodium chloride (14.0 g) in water (160 ml), which is cooled to 5°C. the Reaction vessel was washed with 40 ml of THF and the mixture is transferred into a flask for damping. Hydrated mixture is heated to 20°C and the layers separated. The organic layer is washed with a solution of sodium bicarbonate (NaHCO3) (9.6 g NaHCO3/160 ml of water). The organic layer add toluene (120 ml) and the mixture distilled until then, until capacity is not reached temperature equal 90,2°C. Add heptane (439 ml) and the mixture is cooled at a speed of 0.5°C/min up to 5°C, at this time, crystals are formed. The mixture is filtered through a polypropylene sieve and a solid residue on the filter was washed with 100 ml of a mixture of 50:50 (vol/vol) heptane:toluene. The solid is dried in a vacuum furnace by passing nitrogen over night at 50°C. the Product is obtained as white solids (19,75 g, yield 52%). Mass spectrometry high-resolution computed for C16H16NO2: 254,1193 (M+H)+found 254,1181.

Stage 2 (alternate method): Obtaining 4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazol,2

In a 500 ml reactor equipped with a casing, a mechanical stirrer, thermocouple and inlet for nitrogen at a positive pressure, load the reaction of 1,2-diphenylethanone, (3.4 grams). Add tetrahydrofuran (THF) (209 ml), with stirring, to dissolve the solids. The reaction mixture is cooled until then, until the temperature of the load -15°C. In the reaction capacity load n-exility in hexane (131 ml, 2,3M), while maintaining the temperature below 10°C. After complete addition, the mixture is cooled to a temperature load -15°C. As quickly as possible, add ethyl acetate (80 ml). The reaction mixture is brought to 0°C, and then transferred into a mixture of sodium chloride (14.0 g) in water (160 ml), which is cooled to <5°C. the mixture during blanking support at temperatures below 15°C. the Reaction container was washed with 40 ml of ethyl acetate and this mixture is transferred into a flask for damping. Hydrated mixture is heated to 20°C and the layers separated. The organic layer is washed with a solution of sodium bicarbonate (NaHCO3) (9.6 g NaHCO3/160 ml of water). To the organic layer, add toluene (120 ml) and the mixture distilled until then, until you remove 67% of the tank's contents (temperature ˜90-93°C). Add heptane (439 ml) and the mixture is cooled at a speed of 0.5°C/min up to 5°C, at this time, crystals are formed. The mixture is filtered and the solid residue on the filter was washed with 100 ml of a mixture of 50:50 (vol/vol) heptane:toluene. The solid is dried in a vacuum furnace by passing nitrogen over night at 50ଌ. The product is obtained as white solids (regular production yield: 59%). Mass spectrometry high-resolution computed for C16H16NO2: 254,1193 (M+H)+found 254,1181.

Stage 3: Obtain 4-(5-methyl-3-phenyl-4-isoxazol)benzosulfimide (valdecoxib,1)

4,5-Dihydro-5-methyl-3,4-diphenyl-5-isoxazole (50.0 g, 0,197 mol) are loaded into a 500 ml reactor, which is cooled to 5°C. Triperoxonane acid (38,3 ml, 0,496 mol) download with stirring in a reactor, and the solution having a temperature of 35°C, cooled to ˜5°C. Slowly added chlorosulfonic acid (232 g, 1,99 mol), to control the selection of hydrogen chloride (HCl), and during add support temperature <25°C. Then the reaction solution is heated to 60°C and maintained at 60°C for 2.5 hours. After cooling the reaction solution to 0°C it is added slowly to stir at 2-25°C mixture of toluene (172 ml) and water (150 ml). The reactor is washed with a mixture of toluene (18,4 ml) and water (50 ml), which is then added to the mixture to absorb. Toluene layer is extracted with water (50 ml) and cooled to 0.2°C. Concentrated ammonium hydroxide (62 ml, 1,60 mol) is added slowly while cooling, maintaining during the addition the temperature ˜10-15°C. the Mixture is slowly heated to 35°C and maintained at this the temperature for ˜ 40 minutes. Add isopropanol (240 ml) and the reaction mixture is again heated to 35°C and incubated at 35°C for 90 minutes. The crystalline mixture is slowly cooled to 20°C and the crude product is filtered, washed with isopropanol (100 ml) and water (100 ml). Wet the filter cake is transferred into 500 ml of the mold and dissolved in methanol (350 ml) at ˜58°C. In a methanol solution was added water (92 ml) and the solution heated to ˜70°C. the solution is slowly cooled to 50°C, incubated for 60 minutes and then cooled to 5°C. After one hour at 5°C crystalline product is filtered, the filter cake washed with 75%-Noah mixture of methanol-water (100 ml) and dried in vacuum at ˜70°C. using differential scanning calorimetry (DSC) to find the boiling point of 171 to 174°C (determined at the speed of 10 degrees C/min).

Example 2

Obtaining N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide (parecoxib,1a).

4-(5-methyl-3-phenyl-4-isoxazolyl)benzosulfimide (10.0 g, to 0.032 mol) and propionic anhydride (40 ml, 0.31 mol) are loaded into a 500 ml reactor. The suspension is stirred and heated to 50°C. One portion add sulfuric acid (40 μl, 0.8 mmol). All solids dissolved and the mixture is heated to 55.5°C within 10 minutes after the add is placed. Then the reaction mixture is heated to 80°C and incubated for approximately 10 minutes. The heating stops, the mixture is allowed to cool to 50°C and incubated for about 60 minutes; the solid begins to crystallize from the reaction mixture at about 65°C. the Mixture is slowly cooled to 0°C and maintained at 0°C for about 60 minutes. The solid is filtered off under vacuum. Wet the filter cake is washed with two 45-ml portions of tert-butyl ether and dry the residue collected at ambient temperature for about 15 minutes. The solid is optionally dried in a vacuum furnace by passing nitrogen at 60°C for 18 hours, getting a solid product (8,72 g exit 75%). Maximum endotherm according to DSC for parecoxib with a high melting point equal 168,95. Maximum endotherm according to DSC for parecoxib with low melting point equal 147,44.

Example 3

Obtaining the sodium salt of N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide (parecoxib sodium1b).

N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide (10.0 g, 0,026 mol) and 160 ml of absolute ethanol is loaded into a 500 ml reactor. The suspension is heated to 45°C, incubated for 30 minutes in a reaction chamber add a solution priblizitelen is 5 mass percent of sodium hydroxide in ethanol (22,4 g, 0,028 mol) at 45°C. After complete addition, the solution tatrallyay sodium salt of N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide to initiate crystallization. The temperature of the reaction mixture increased to 50°C and incubated the mixture for 30 minutes the Mixture is slowly cooled to 0°C and incubated for about 60 minutes, the Solid is collected by vacuum filtration. The wet precipitate on the filter is washed twice with two 20-ml portions of absolute ethanol and collect dry the residue under vacuum bell jar by blowing with nitrogen. The solid is optionally dried in a vacuum furnace by passing nitrogen at 120°C overnight with obtaining solid product (9,11 g, yield 85%). The maximum of the endotherm, according to DSC, for the form I parecoxib sodium equal 274,28°C.

Example 4

Getting 5-methyl-3,4-diphenylethanol,3

4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazole (15,0 grams, 0,059 mol) are loaded into a 250 ml flask. Add triperoxonane acid (10.5 ml) under stirring and watching exothermic heating to 44°C. the Solution is heated to a temperature in the range between 44 and 57°C, for 60 minutes, cooled to room temperature and subjected to vacuum distillation to remove triperoxonane acid. The residue is dissolved in 100 ml of toluene and distilled at vacuu the E. The process is repeated a second time with getting a semicrystalline concentrate. The concentrate is dissolved in 250 ml of hot heptane, decanted into a 500 ml flask, cooled to room temperature and stand for 18 hours. The crystalline precipitate on the filter break and the crystals filtered off. The filter cake is dried to obtain 10,19 g (yield 73% of the mass) of the desired product. Melting point according to DSC: 95,55-96,24°C at a speed of 10°C/min, in an unpackaged the mould.

Example 5

Getting 4-(5-methyl-3-phenyl-4-isoxazolyl)benzosulfimide,6

4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazole (13,0 grams, 0,0513 mol) is loaded into a 200 ml flask equipped with a guard, which is cooled by passing liquid having a temperature of 0.2°C. Triperoxonane acid (9.1 ml, amount of 0.118 mol) load to the solid product for reconstitution with 38,6°C. the Solution is cooled to 2.1°C and slowly added chlorosulfonic acid (34,7 ml, 0,522 mol)while maintaining the temperature below 14°C. The solution is heated to 60°C, incubated for 2.5 hours, cooled to 20°C and transferred into a 125 ml addition funnel. Toluene (52 ml) and water (52 ml) was loaded into a 200 ml reactor, equipped with a casing, and cooled to 4°C. Then the reaction solution is slowly added to 200 ml reactor, equipped with a cover, while p is deriva temperature below 20° C. Multiphase mixture is heated to 20°C and transferred into a 250 ml separating funnel. Add toluene (50 ml) and water (10 ml) and the mixture shaken. The settling of the mixture leads to the appearance of two muddy phases. Toluene phase is twice washed with 15 ml of water, transferred into a 250 ml flask, washing with 20 ml of toluene, and subjected to vacuum distillation with the receipt of 17.4 g of oil. After initiation of the crystallization with a glass rod and cooling add heptane (20 ml) to a crystalline mass, which break with obtaining powder. No white powder is filtered off. Portions of heptane, 50 ml is used to facilitate transfer of solids on the filter. The filter cake is dried in a vacuum oven (35° (C) obtaining of 13.6 g (79,4% of the mass) sulphonylchloride in the form of a mixture of 85:15 para - and meta-isomers. HRMS calculated for (M+1) C16H13NO3Cl: 334,0305; found (M+1): 334,0309.

Example 6

Getting 4-(5-methyl-3-phenyl-4-isoxazolyl)benzosulfimide,6

5-methyl-3,4-diphenylethanol (5.0 g, 0,0213 mol) are loaded into a 100 ml reactor, equipped with a casing which is cooled by passing liquid having a temperature of 0.2°C. Triperoxonane acid (3.5 ml, 0.045 mol) load to the solid substance to obtain a solution with 3°C. Slowly added chlorosulfonic acid (13.3 ml, 0,201 mol), while maintaining the reaction temperature the lower the 20° C. the Solution is heated to 60°C and incubated for 2.2 hours. Then the solution is cooled to 6°C and transferred into a 60 ml addition funnel. Toluene (20 ml) and water (20 ml) was loaded into a 100 ml reactor equipped with a jacket, and cooled to 6°C. Then the reaction solution is slowly added to 100 ml reactor, equipped with a cover, while maintaining the temperature below 16°C. Multiphase mixture is transferred into a 125 ml separating funnel. Add toluene (20 ml) and water (5 ml) and the mixture shaken. The settling of the mixture results in two turbid phases. Toluene phase is washed with twice 5 ml of water, transferred into a 125 ml flask, rinsing 17 ml of toluene, and subjected to vacuum distillation to obtain semi-crystalline concentrate. The concentrate is dissolved in 100 ml of toluene and subjected to vacuum distillation to obtain oil. After initiation of the crystallization with a glass rod, add heptane (11 ml) and the mass break with getting not quite white powder. Solids filtered off. Portions of heptane and 25 ml used to facilitate transfer of solids on the filter. The filter cake is dried to obtain 7,07 g (100% of the mass) sulphonylchloride in the form of a mixture of 85:15 para - and meta-isomers. HRMS calculated for (M+1) C16H13NO3Cl: 334,0305; found: (M+1): 334,0299.

Example 7

Getting 4-(5-methyl-3-phenyl-4-isoxazol)benzosulfimide KIS is the notes

4-(5-Methyl-3-phenylisoxazol)benzosulphochloride (39.6 grams, 0.11 mole), water (99.5 ml, 5.5 mol) and tetrahydrofuran (558 ml) was loaded into a 1-liter flask and heated at boiling temperature under reflux overnight. After cooling to ambient temperature the solvent is removed under pressure. The remaining yellow oil is additionally dried in a high vacuum. The obtained solid substance is poured toluene (500 ml) and heated at boiling temperature under reflux. After about 30 minutes, the solid is melted and collected in the bottom of the flask. The mixture is stirred at the boiling point under reflux for 4 hours, cooled to room temperature and stirred over night. Solids filtered off, within a short period of time air-dried and crushed into powder. The powder is suspended in toluene (500 ml), heated to the boiling temperature under reflux and re utverjdayut during cooling to room temperature. The solids are filtered and dried, obtaining 23.8 grams of product with a melting point 174-176°C.

1. The method of producing compound [isoxazol-4-yl]benzosulfimide structural formula 1

including interaction connection predecessor, using the data from the group consisting of compounds of formula 2 and formula 3

with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product;

interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1.

2. The method according to claim 1, where halogencontaining acid selected from the group consisting of bromsulphalein acid and chlorosulfonic acid.

3. The method according to claim 1, where galogenarenov acid is a chlorosulfonic acid.

4. The method according to claim 1, where the source of ammonium is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

5. The method according to claim 1, where the source of ammonium is an ammonium hydroxide.

6. The method according to claim 1, where the source of ammonium is an anhydrous ammonia.

7. The method of obtaining the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1A

including interaction connection-precursor selected from the group consisting of compounds of formula 2 and formula 3

with halogencontaining acid in the presence triperoxonane acid with obtaining Gal who healthinsurnace product;

interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1.

the interaction of compounds [isoxazol-4-yl]benzosulfimide with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1A.

8. The method according to claim 7, where halogencontaining acid selected from the group consisting of bromsulphalein acid and chlorosulfonic acid.

9. The method according to claim 7, where galogenarenov acid is a chlorosulfonic acid.

10. The method according to claim 7, where the source of ammonium is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

11. The method according to claim 7, where the source of ammonium is an ammonium hydroxide.

12. The method according to claim 7, where the source of ammonium is an anhydrous ammonia.

13. The method according to claim 7, where propionyloxy agent selected from the group consisting of anhydride propionic acid, Propionaldehyde, proponiamo of tiefer, propionylcarnitine and N-propylimidazol.

14. The method according to item 13, where propionyloxy agent is Propionaldehyde.

15. The method according to 14, where propionyloxy agent is propionitrile.

16. The method according to item 13, where PR is pioneersi agent is an anhydride of propionic acid.

17. The method according to item 13, where the anhydride of propionic acid is a propionic anhydride.

18. The method of obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1b

including interaction connection-precursor selected from the group consisting of compounds of formula 2 and formula 3

with halogencontaining acid in the presence triperoxonane acid with getting halogencontaining product;

interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1

the interaction of compounds [isoxazol-4-yl]benzosulfimide structural formula 1 with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1A

followed by the interaction of the compounds of formula 1A with a sodium base with obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1b.

19. The method according to p where halogencontaining acid selected from the group consisting of bromalite the Oh of the acid and chlorosulfonic acid.

20. The method according to p where galogenarenov acid is a chlorosulfonic acid.

21. The method according to p, where the source of ammonium is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

22. The method according to p, where the source of ammonium is an ammonium hydroxide.

23. The method according to p, where the source of ammonium is an anhydrous ammonia.

24. The method according to p where propionyloxy agent selected from the group consisting of anhydride propionic acid, Propionaldehyde, proponiamo of tiefer, propionylcarnitine and N-propylimidazol.

25. The method according to paragraph 24, where propionyloxy agent is Propionaldehyde.

26. The method according A.25 where propionyloxy agent is propionitrile.

27. The method according to paragraph 24, where propionyloxy agent is an anhydride of propionic acid.

28. The method according to paragraph 24, where the anhydride of propionic acid is a propionic anhydride.

29. The method according to p, where sodium base selected from the group consisting of sodium hydroxide, sodium alkoxide, sodium hydride and sodium carbonate.

30. The method according to clause 29, where the sodium base is a hydroxide of sodium.

31. The method of producing compound [isoxazol-4-yl]benzosulfimide structural formula 1

kiuchumi

education derived compounds diphenylethanone by reacting compounds 1,2-diphenylethanone source hydroxylamine;

interaction derived compounds reaction with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene;

interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product

and interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1.

32. The method according to p, where the source of hydroxylamine is an aqueous solution containing hydroxylamine.

33. The method according to p, where the source of hydroxylamine is an aqueous solution containing hydroxylamine and a weak acid.

34. The method according to p, where the weak acid is a carboxylic acid.

35. The method according to p, where the carboxylic acid is alkalicarbonate acid.

36. The method according to p where alkalicarbonate acid selected from the group consisting of formic acid, acetic acid and propionic acid.

37. The method according to p where alkalicarbonate acid is an acetic acid.

38. The method according to p, where source is hydroxylamine is an aqueous solution, containing hydroxylamine and base, combined with a weak acid.

39. The method according to § 38, where the basis, combined with a weak acid is a sodium acetate.

40. The method according to p, where the source contains hydroxylamine salt is hydroxylamine and deprotonized base.

41. The method according to p, where the salt of the hydroxylamine selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate.

42. The method according to paragraph 41, where the salt of the hydroxylamine is hydroxylamine hydrochloride.

43. The method according to p where deprotonate base selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium acetate.

44. The method according to p where deprotonate base is a sodium acetate.

45. The method according to p, where the source contains hydroxylamine hydroxylamine and acetic acid.

46. The method according to p, where a strong base selected from the group consisting of Nitidulidae, argillite, arylalkylamine and alkylate.

47. The method according to p, where a strong base is Nitidulidae.

48. The method according to p, where a strong base is sitedisability.

49. The method according to item 46, where a strong base is a C1about10alkylate.

50. The method according to p, where a strong base is the Wallpaper utility.

51. The method according to p, where a strong base is exility.

52. The method according to p, where a strong base is satillite.

53. The method according to p, where a strong base is octillery.

54. The method according to p where acetylide agent selected from the group consisting of alkyl acetate, acetic anhydride, N-alkyl-N-alkoxyacetic and acetylchloride.

55. The method according to item 54, where acetylide agent represents a C1about6alkyl acetate.

56. The method according to p where acetylide agent selected from the group consisting of methyl acetate, ethyl acetate, propyl and butyl acetate.

57. The method according to p, where the alkyl acetate is the acetate.

58. The method according to p where acetylide agent is acetylsalicinic.

59. The method according to § 58, where acetylsalicinic is acetylchloride.

60. The method according to p where acetylide agent is an acetic anhydride.

61. The method according to p where halogencontaining acid selected from the group consisting of bromsulphalein acid and chlorosulfonic acid.

62. The method according to p where galogenarenov acid is a chlorosulfonic acid.

63. The method according to p, where the source of ammonium is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

64. The method according to p where East is CNIC ammonium represents ammonium hydroxide.

65. The method according to p, where the source of ammonium is an anhydrous ammonia.

66. The method of obtaining the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1A

including

the formation of a derivative diphenylethanone by reacting compounds 1,2-diphenylethanone source hydroxylamine;

the interaction of the oxime with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene;

interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product;

interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1

and the interaction of the compounds [isoxazol-4-yl]benzosulfimide formula 1 with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1A.

67. The method according to p, where the source of hydroxylamine is an aqueous solution containing hydroxylamine.

68. The method according to p, where the source of hydroxylamine is an aqueous solution, the content is the overall hydroxylamine and a weak acid.

69. The method according to p, where the weak acid is a carboxylic acid.

70. The method according to p, where the carboxylic acid is alkalicarbonate acid.

71. The method according to p where alkalicarbonate acid selected from the group consisting of formic acid, acetic acid and propionic acid.

72. The method according to p where alkalicarbonate acid is an acetic acid.

73. The method according to p, where the source of hydroxylamine is an aqueous solution containing hydroxylamine and base, combined with a weak acid.

74. The method according to p, where the basis, combined with a weak acid is a sodium acetate.

75. The method according to p, where the source contains hydroxylamine salt is hydroxylamine and deprotonized base.

76. The method according to item 75, where the salt of the hydroxylamine selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate.

77. The method according to p, where the salt of the hydroxylamine is hydroxylamine hydrochloride.

78. The method according to item 75, where deprotonate base selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium acetate.

79. The method according to item 75, where deprotonate base is a sodium acetate.

80. The method according to item 75, where the source of hydroxylamine contains hydroxylamine acetic acid.

81. The method according to p, where a strong base selected from the group consisting of Nitidulidae, argillite, arylalkylamine and alkylate.

82. The method according to p, where a strong base is Nitidulidae.

83. The method according to p, where a strong base is sitedisability.

84. The method according to p, where a strong base is a1about10alkylate.

85. The method according to p, where a strong base is utility.

86. The method according to p, where a strong base is exility.

87. The method according to p, where a strong base is satillite.

88. The method according to p, where a strong base is octillery.

89. The method according to p where acetylide agent selected from the group consisting of alkyl acetate, acetic anhydride, N-alkyl-N-alkoxyacetic and acetylchloride.

90. The method according to p where acetylide agent is a1about6alkyl acetate.

91. The method according to p where acetylide agent selected from the group consisting of methyl acetate, ethyl acetate, propyl and butyl acetate.

92. The method according to p, where the alkyl acetate is the acetate.

93. The method according to p where acetylide agent is acetylsalicinic.

94. The method according to p where acetylsalicinic is the second acetylchloride.

95. The method according to p where acetylide agent is an acetic anhydride.

96. The method according to p where halogencontaining acid selected from the group consisting of bromsulphalein acid and chlorosulfonic acid.

97. The method according to p where galogenarenov acid is a chlorosulfonic acid.

98. The method according to p, where the source of ammonium is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

99. The method according to p, where the source of ammonium is an ammonium hydroxide.

100. The method according to p, where the source of ammonium is an anhydrous ammonia.

101. The method according to p where propionyloxy agent selected from the group consisting of anhydride propionic acid, Propionaldehyde, proponiamo of tiefer, propionylcarnitine and N-propylimidazol.

102. The method according to p where propionyloxy agent is Propionaldehyde.

103. The method according to 102, where propionyloxy agent is propionitrile.

104. The method according to p where propionyloxy agent is an anhydride of propionic acid.

105. The method according to p, where the anhydride of propionic acid is a propionic anhydride.

106. The method of obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1b

including

the formation of a derivative diphenylethanone by reacting compounds 1,2-diphenylethanone source hydroxylamine;

the interaction of the compounds of the oxime with a strong base and azetiliruet agent with formation of a derivative of diphenylacetylene;

interaction derived diphenylacetone with triperoxonane acid and halogencontaining acid with the formation of halogencontaining product;

interaction halogencontaining product with a source of ammonia to obtain the compound [isoxazol-4-yl]benzosulfimide structural formula 1

the interaction of compounds [isoxazol-4-yl]benzosulfimide with propionyloxy agent to obtain the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1A

and the interaction of the compound N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide sodium base with obtaining the sodium salt of N-[[4-(3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide structural formula 1b.

107. The method according to p, where the source of hydroxylamine is an aqueous solution containing hydroxylamine.

108. The method according to p, where the source of hydroxylamine performance, which defaults to an aqueous solution, containing hydroxylamine and a weak acid.

109. The method according to p, where the weak acid is a carboxylic acid.

110. The method according to p, where the carboxylic acid is alkalicarbonate acid.

111. The method according to p where alkalicarbonate acid selected from the group consisting of formic acid, acetic acid and propionic acid.

112. The method according to p where alkalicarbonate acid is an acetic acid.

113. The method according to p, where the source of hydroxylamine is an aqueous solution containing hydroxylamine and base, combined with a weak acid.

114. The method according to p, where the basis, combined with a weak acid is a sodium acetate.

115. The method according to p, where the source contains hydroxylamine salt is hydroxylamine and deprotonized base.

116. The method according to p, where the salt of the hydroxylamine selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate.

117. The method according to p, where the salt of the hydroxylamine is hydroxylamine hydrochloride.

118. The method according to p where deprotonate base selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium acetate.

119. The method according to p where deprotonate base is a sodium acetate.

120. The way p is p, where the source contains hydroxylamine hydroxylamine and acetic acid.

121. The method according to p, where a strong base selected from the group consisting of Nitidulidae, argillite, arylalkylamine and alkylate.

122. The method according to p, where a strong base is Nitidulidae.

123. The method according to p, where a strong base is sitedisability.

124. The method according to p, where a strong base is a C1about10alkylate.

125. The method according to p, where a strong base is utility.

126. The method according to p, where a strong base is exility.

127. The method according to p, where a strong base is satillite.

128. The method according to p, where a strong base is octillery.

129. The method according to p where acetylide agent selected from the group consisting of alkyl acetate, acetic anhydride, N-alkyl-N-alkoxyacetic and acetylchloride.

130. The method according to p where acetylide agent represents a C1about6alkyl acetate.

131. The method according to p where acetylide agent selected from the group consisting of methyl acetate, ethyl acetate, propyl and butyl acetate.

132. The method according to p, where the alkyl acetate is the acetate.

133. The method according to p where acetylide agent performance, which provides acetylsalicinic.

134. The method according to p where acetylsalicinic is acetylchloride.

135. The method according to p where acetylide agent is an acetic anhydride.

136. The method according to p where halogencontaining acid selected from the group consisting of bromsulphalein acid and chlorosulfonic acid.

137. The method according to p where galogenarenov acid is a chlorosulfonic acid.

138. The method according to p, where the source of ammonium is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

139. The method according to p, where the source of ammonium is an ammonium hydroxide.

140. The method according to p, where the source of ammonium is an anhydrous ammonia.

141. The method according to p where propionyloxy agent selected from the group consisting of anhydride propionic acid, Propionaldehyde, proponiamo of tiefer, propionylcarnitine and N-propylimidazol.

142. The method according to p where propionyloxy agent is Propionaldehyde.

143. The method according to p where propionyloxy agent is propionitrile.

144. The method according to p where propionyloxy agent is an anhydride of propionic acid.

145. The method according to p, where the anhydride of propionic acid is a propionic anhydride.

146. The method according to p, where the sodium base is chosen from the group, ostoja of sodium hydroxide, the sodium alkoxide, sodium hydride and sodium carbonate.

147. The method according to p, where the sodium base is a hydroxide of sodium.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

The invention relates to new substituted the isoxazoles of General formulas I, II, III, IV, V, where R1selected from lower alkyl, carboxyamide, alkoxycarbonyl, aminocarbonyl, aminocarbonylmethyl and so on; R2choose from alkylsulfonyl, hydroxysulfonic and aminosulfonyl; R3selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from alkyl, cyano, halogenoalkane, hydroxyalkyl and so on; provided that R2is aminosulfonyl, if R2- substituted phenyl radical is in the 3-position isoxazol; R4selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyethyl and so on; R5selected from methyl, hydroxy and amino; R6selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from lower alkylsulfonyl, lower alkyl, cyano, lower halogenoalkane and so on; R7selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyl and so on; R8represents one or more radicals and so on

The invention relates to a new derivative of pyrazole, substituted bentilee group in position 4 of the pyrazole ring, and herbicide

The invention relates to new isoxazol derivative, compositions containing them, methods of obtaining and use as herbicides

The invention relates to new derivatives of 4-benzoimidazole formula I where R is hydrogen or-CO2R4; R1- C3-6-cycloalkyl; R2- halogen, n-alkyl, possibly substituted by one or more halogen atoms, or5, -S(O)pR6; R3IS-S(O)qR7; X IS -(CR9R10)t-; n = 0, 1, and 2; when n is greater than 1, the groups R2may be the same or different; R4, R5and R6-n-alkyl; R7-n-alkyl, possibly substituted by one or more atoms of hydrogen, C3-C6alkenyl straight chain or phenyl; R9and R10is hydrogen or C1-C6-alkyl straight chain; p and q = 0, 1, or 2; t is an integer from 1 to 4, when t > 1, group-CR9R10may be the same or different; or acceptable for agriculture salt

The invention relates to new derivatives of 4-benzoimidazole, containing compositions, methods for their preparation, intermediate substances for their preparation and their use as herbicides

The invention relates to a new simple cyclohexanehexol esters and herbicide compositions on their basis

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of aromatic sulfonyl halides by interaction of substituted phenolic compound with halogensulfonic acid and trifluoroacetic acid. Also, invention involves a method for synthesis of 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide of the formula (1) that is useful in treatment of disorders associated with cyclooxygenase-2 and involves interaction of a precursor-compound chosen from group consisting of compounds of the formula (2) and formula (3) with halogensulfonic acid in the presence of trifluoroacetic acid to yield a halogensulfonated compound, and interaction of a halogensulfonated compound with ammonium source to yield compound (isoxazol-4-yl)-benzenesulfonamide of the structural formula (1).

EFFECT: improved method of synthesis.

147 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to parecoxib sodium salt in crystalline form that possesses properties of selective inhibitor of cyclooxygenase-2 (COX-2) and can be used in treatment of, for example, inflammatory diseases and pain. Proposed crystalline forms show characteristic peaks of powder X-roentgenogram obtained with using Cu-source of radiation and expressed as angles 2θ and chosen from groups consisting of at least values 5.6; 9.6; 11.0 and 14.5 ± 0.2 angle (form A), and 4.2; 8.3; 12.4; 16.7; 17.5; 20.8 and 24.7 ± 0.2 angle (form B), and 8.8; 11.3; 15.6; 22.4; 23.5 and 26.4 ± 0.2 angle (form E) and wherein each form is anhydrous and non-solvated. Also, invention relates to a method for preparing crystalline form A and to a pharmaceutical composition.

EFFECT: improved preparing method, valuable properties of drug.

21 cl, 5 tbl, 12 dwg, 1 sch, 7 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

Dpp-iv inhibitors // 2345067

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of general formula (I) Z-C(R1R2)-C(R3NH2)-C(R4R5)-X-N(R6R7) (I), or its pharmaceutically acceptable salt which is different because Z represents phenyl; where Z can be substituted with one or more R8, where R8 represents halogen; R1, R4 represent H; R2, R5 represent H; R3 represents H; X is selected from group consisting of S(O)2 and C(O); R6, R7 are independently selected from group consisting of H, (C(R29R30))m-X1-Z1 and (C(R31R32))n-X2-X3-Z2 and C1-4alkyl, which carries substitution with one or more R29a, where R29a is independently selected from group consisting of R29b and Z1, on condition that R6 and R7 are selected in such way that R6 and R7 were not simultaneously independently selected from group consisting of H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2; R29 R29b, R30, R31, R32 are independently selected from group consisting of H, C1-6alkyl and N(R32a)-C1-6alkyl; R32a represents C1-6alkyl; m is 0, 1 or 2; n is 2; X1 is independently selected from group consisting of covalent bond, -C1-6alkyl and -C1-6alkyl-N(R33)-; X2 represents -N(R35)-; X3 represents -C(O)-; R33 represents C1-6alkyl; R35 represents H; Z1, Z2 are independently selected from group consisting of Z3 and -C(R37a)Z3aZ3b; R37a represents H; Z3, Z3a, Z3b are independently selected from group consisting of T1, T2, C1-6alkyl, C1-6alkyl-T1 and C1-6alkyl-T2; T1 represents phenyl; where T1 is optionally substituted with one or more R38; R38 being independently selected from group consisting of halogen, CN, R39, C(O)NH2, S(O)2NH2, OT3, C(O)N(R40)T3 and T3, T2 is selected from group consisting of C3-7cycloalkyl, indanyl, tetralinyl, heterocycle and heterobicycle, T2 optionally carries substitution with one or more R41, where R41 is independently selected from group consisting of halogen, R42, OH and T3; R39 is selected from group consisting of C1-6alkyl, O-C1-6alkyl, S-C1-6alkyl, C(O)N(R44)-C1-6alkyl, S(O)-C1-6alkyl and S(O)2-C1-6alkyl, where each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F, N(R46R47) and T3; R42 represents C1-6alkyl, each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F; R40, R46, R47 are independently selected from group consisting of H and C1-6alkyl; R44 represents H; T3 is selected from group consisting of T4 and T5; T4 represents phenyl, where T4 optionally carries substitution with one or more R51, where R51 is independently selected from group consisting of halogen, OR52, S(O)2N(R52R53), C1-6alkyl; R52, R53 are independently selected from group consisting of H and C1-6alkyl; T5 is selected from group consisting of heretocycle C3-7cycloalkyl, where T5 optionally carries substitution with one or more R54, where R54 represents C1-6alkyl; where heterocycle represents ring of cyclobutane, cyclopentane, cyclohexane, which can contain double bonds in number up to maximal, or aromatic or non-aromatic ring which is fully or partially saturated or unsaturated, and in which at least one carbon atom, maximally up to four carbon atoms, are substituted with heteroatom, selected from group including oxygen and nitrogen, and where ring is bound with remaining part of molecule through carbon or nitrogen atom; where heterobicycle represents heterocycle as stated above, which is condensed with phenyl or other heterocycle with formation of bicyclic ring system, on condition that the following compound is excluded from claim:3-amino-N-cyclohexyl-4-phenylbutyramide. Invention also relates to pharmaceutical composition based on compound of general formula (I) and to their application for manufacturing medication for treatment and/or prevention of conditions during which it is desirable to inhibit DPP-IV.

EFFECT: obtaining novel group of compounds possessing useful biological properties.

26 cl, 8 tbl, 193 ex

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

Up!