The method of obtaining acetylene derivatives chromane or thiochroman

 

(57) Abstract:

Usage: in medicine, in particular as cytotoxic funds on the basis of acetylene derivatives Romana. The inventive product - acetylene derivatives chromane f-ly 1, contained in the description, where R1, R2, R4, R5=C1-C6-alkyl; R3= H or C1-C6-alkyl; X = o or S; A is phenyl or pyridyl; n = o; B = C(O)OR6; R6=C1-C6-alkyl; as well as derivatives chromane or thiochroman f-crystals II, contained in the description, where R1, R2, R4, R5=C1-C6-alkyl; R3= N or C1-C6-alkyl; X = o or S; Z = N. Reagent 1: connection f-ly 1, where R1-R5see above; Z = H or a metal ion, or associated with the anion of the metal ion, the latter being formed with a etinilnoy group salt compounds f-ly 1. Reagent 2: compound f-ly III, contained in the description: X-A-(CH2)n-B , where X = Hal, A and B, n - see above. Reaction conditions: in the presence of one or two catalysts, i.e., when Z = H, then use the catalyst - iodide copper (1) and Pd(PQ3)2Cl2where Q is phenyl, and in the case when Z = ZnCL(+), the catalyst is Pd(q3)4where Q is phenyl. Connection f-crystals 1 vyzyvaetsya the method of production of new compounds, which possess biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity.

Known tetrahydronaphthalene with ethenylbenzene acid, and compounds in which three olefinic link in the acid part retinova acid substituted ethynylphenyl group. These compounds have biological activity similar to the activity retinova acid.

Also known such disubstituted acetylene compounds in which one of the substituents azetidinol (ethyl) group represents a substituted phenyl group, and the second Deputy is substituted or unsubstituted chromanol, thiochroman or tetrahydropyranyl group. These compounds have biological activity similar to the activity retinova acid.

Known types disubstituted acetylene compounds in which one Deputy acetylene (ethyl) group is a substituted phenyl or substituted heteroaryl group, and the other Deputy - substituted or unsubstituted who uchitelnoj redenominate-like activity.

Activity, like retinova acid, specialists usually associated with useful biological activity, specifically compounds with retrocyclin-like activity, are used as regulators of cell proliferation, and particularly as agents for treating dermatoses, such as acne, disease Daria, psoriasis, ichthyosis, eczema, atopic dermatitis and epithelial malignant diseases, for the treatment of arthritis and other immune disorders, such as lupus arimatsu, to accelerate wound healing, for treating syndrome Sjogren and to eliminate the effects of sun damage to the skin.

As for the processes of the proposed synthesis that involve either the formation of acetylene (etinilnoy) function in the compounds according to this invention, or a combination of these compounds, which already have etinilnoy function, with galoidzamyescyennykh a phenyl or heteroaryl group.

The invention relates to a new method of obtaining disubstituted acetylene compounds with biological activity similar to the activity retinova acid, and having as one substituent of substituted or unsubstituted chromanol, thiochroman and olsavica in the synthesis of these biologically active disubstituted acetylenes.

In accordance with the invention to carry out the reaction of 6-thiochroman-Edinboro, 6-chromanol-Edinboro and 6-tetrahydroquinoline-atenololo the compounds of formula II or the corresponding metal salts with the corresponding galoidzamyescyennykh phenyl or heteroaryl compound of formula III to obtain compounds of formula I. the compounds of formula I have valuable biological activity, such retinova acid or easy standard operations, for example by esterification, diesterification, homologation, oxidation, recovery, amidation, and similar methods can be converted into compounds with activity similar to the activity retinova acid.

Reaction scheme I

where R1, R2, R4and R5- may be the same or different and represent a1-C6-alkyl;

R3is a hydrogen atom or alkyl with 1-6 carbon atoms;

X is oxygen or sulfur;

Z is hydrogen, metal ion or metal ion associated with the anion, and this metal ion forms a salt with etinilnoy connection group;

And is phenyl or pyridyl;

n is an integer equal to 0;

In - group R6where R6- C1-C6-linename formula III is carried out in accordance with the proposed method in the presence of copper iodide (I), a in the presence of Pd(PQ3)2Cl2where Q is phenyl, when Z is hydrogen and in the presence of Pd(PQ3)4where Q is phenyl, or a similar complex, when Z is a metal ion, such as ZnCl+.

Compounds corresponding to formula II, represent another aspect of the invention. These compounds are used as intermediates for the synthesis of biologically active and valuable retinochoroidopathy compounds of formula I.

Pharmaceutically acceptable salt can be obtained for any connection made in accordance with the present invention, provided that the compound has a functional capability of forming such salt, for example an acid or amine function. Pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not have a negative or adverse effect on the object to which they are directed, in use conditions.

Such salt may be derived from any organic or inorganic acid or base. Salt may be a mono - or polyvalent ion. Of particular interest in the case of acid functions are inorganic ions, sodium, Kalamanov such as mono-, di-, trialkylamine or ethanolamines. Salt can also be obtained from caffeine, trometamina and similar molecules. In that case, if there is nitrogen, sufficient alkali to form molecular salts with acids, such salts can be any inorganic or organic acids or alkylating agent, such as methyliodide. Preferred salts are those derived from inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Can also be used any number of simple organic acids such as mono-, di - or tri-basic acids.

Compounds that are preferably used in the process of the proposed synthesis for the introduction of substituted chromanol, substituted thiochroman and substituted tetrahydropyranyl group as one of the Vice atenolol group of biologically active compounds, and which are therefore preferred intermediate compounds in the invention meets the formula IV

< / BR>
Such preferred compounds and intermediate substances are the following:

Connection 1: X=S; R1=R2=CH3, R3=R4=R5=H.

1=R2=R4=R5=CH3, R3=H.

Compound 4: X=O; R1=R2=CH3, R3=R4=R5=H.

Connection 5: X=O; R1=R2=R4=R5=CH3, R3=H.

Compound 6: X=S; R1=R2=R3=R4=R5=CH3.

Compound 7: X=O; R1=R2=R3=R4=R5=CH3.

4,4-dimethyl-6-utilitiarian (compound 1)

4,4,7-trimethyl-6-utilitiarian (compound 2)

2,2,4,4-tetramethyl-6-utilitiarian (compound 3)

4,4-dimethyl-6-itineray (compound 4)

2,2,4,4-tetramethyl-6-itineray (compound 5)

2,2,4,4,7-pentamethyl-6-tinytiger - EN (compound 6)

2,2,4,4,7-pentamethyl-6-itineray (compound 7).

In the proposed method is also preferred metal salt, preferably zinc, as preferred intermediate compounds.

The compounds of formula II and their salts of metals such as zinc, preferably the compounds of formula IV (or their salts), interact with the compounds of the formula III to obtain compounds of formula I.

When the preferred compounds of formula IV interact with compounds of formula III, then in recip is eleniak, data for compounds 1-7.

The reaction conditions for the reaction of a combination of compounds of the formula II with compounds of formula III in accordance with the proposed method as well as processes for the synthesis of compounds of formula II in detail in the following.

In relation to the biological activity of compounds of the formula I obtained in accordance with the proposed method (using intermediate compounds according to the invention), requires the following explanations. The activity of these compounds, such activity retinova acid, confirmed by a standard measure of activity retinova acid, including action retinova acid on ornithindecarboxilase. Known for work that establishes a connection between retinova acid and reduced cell multiplication. In this work revealed that the activity of interdiscursivity (ODS) increases the propensity for the biosynthesis polyamine. It was found that the increased synthesis of polyamines can be correlated with cell proliferation. Thus, suppression of democratic activity may change piperazinone cells. Although unknown all causes of the increase in ODS-activity. It is known however, that 12-O-tetradecanoylphorbol-13-acetate (TN) of the invention also inhibit TN-stimulation of the UDF, as illustrated by the experiences of the known methods.

As an example activity, such activity retinova acid, you should specify that in the experiment, carried out in accordance with the method of Berman and Botella, the following examples of compounds (compounds 10, 11 and 12) obtained in accordance with the proposed method, cause 80% suppression of TN-called UDF-activity at the following concentrations (IC80): Compound IC80conc.mmol 10 0,69 11 0,13 12 0,12

Compounds 10, 11 and 12 are characterized with reference to formula I:

The connection 10: X=S, R1=R2=R4=R5=CH3< / BR>
R3=H, A-(CH2)n-B=ethyl 6-nicotinate

The connection 11: X=O, R1=R2=R4=R5=CH3< / BR>
R3=H A-(CH2)n-B=ethyl 6-nicotinate

Connection 12 X=O, R1=R2=R3=R4=R5=CH3A-(CH2)n=B=ethyl-6-nicotinate

Due retinopathy activity of the compounds of formula III can be used long-term or topically for the treatment of various diseases.

Compounds according to the invention, which correspond to the formula II and is a key intermediate compounds in stages of the proposed synthesis, can be floor is of the compounds of formulas II and I, with strict adherence to the described method. These conditions are specific examples of implementation that are applicable to any and all compounds of formula II and I. it is Obvious that the described stages can be changed and/or adjusted without deviating from the scope and meaning of the proposed method. It should also be borne in mind that some of the stages and methods used in the examples, compounds of formula II are new and innovative.

With reference to the compound of formula II, the reaction scheme 2 illustrates an example of synthesis, when X=sulfur; R4and R5- hydrogen atoms.

Reaction scheme 2

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Considering the reaction scheme 2, thiophenol 13, which may have R3-Deputy (defined above as the hydrogen atom or lower alkyl), alkylate, preferably in hard alkaline conditions, such as caustic soda, in a polar solvent (acetone at room temperature) of the compound 14, which is either 1-bromo-3-methyl-2-butene (R1and R2- methyl firm Aldrich), or its derivative, or where R1or R2or both are alkilani other than methyl. Received alkilirovanny thiophenol (sulfide, compound 15) is then subjected to cyclization reaction according to the Friedel-Crafts or in the toluene, in the presence of phosphoric anhydride and phosphoric acid. Obtained in accordance with scheme 2 thiochroman (compound 16) does not contain substituents in position 2 and preferably in accordance with scheme 2 R1and R2- mately and R3- hydrogen.

The connection 16 will acetimidoyl by Friedel-Crafts or under similar conditions, preferably by acetylchloride (AlCl3CH2Cl2, boiling under reflux) to give 6-acetyl-thiochroman (compound 17). Acetyl group of compound 17 in turn acetylene (etinilnoy) function using diisopropylamide lithium, or a similar reason at low temperature. The intermediate connection obtained from a connection 17, presumably lithium salt of the corresponding enol (figure 2 not shown), etherification treatment diethylphosphate (or similar compound) and again carry out the reaction at low temperature, for example -78aboutWith diisopropylamide lithium, leading to the formation of a triple bond, presumably during the reaction off, getting a 6-ethynylcyclopentanol derivative (compound 18).

In this regard, it should be noted that the proposed synthesis is not limited and is eposredstvenno in the reaction combinations, described in scheme I, or pre-make it in metal (zinc) salt (compound 19).

Chlorydrique salt (compound 19) was prepared in the absence of water and oxygen. The solvent may be used in anhydrous ether type solvent, such as sulfuric ether or cyclic simple ether, such as furan or Piran, especially tetrahydrofuran. A solution of compound 18 first get in an inert atmosphere (argon or nitrogen) and then add a strong base, such as n-utility (about 10% molar excess). The reaction starts at a lower temperature in the range -10 - +10aboutWith, preferably approximately at 0aboutC. the Reaction mixture is stirred for a short period of time (in the range of 0.5 to 2 h and then treated at about 10% molar excess of fused chloride of zinc dissolved in the reaction solvent. The mixture was stirred additional 1-3 h at approximately the initial temperature, then the temperature was raised to approximately the ambient temperature within 10-40 minutes

Such receiving hloretilnykh salts corresponding to the connection 19 also apply with such modifications, which provide about obtaining the compounds of formula II, when X is sulfur and R4and R5- hydrogen. Shown in figure 3, the sequence of reactions is preferred (but not required) when R3is not a hydrogen/ while scheme 2 preferably osushestvlyaetsya (but not necessarily) when R3- hydrogen.

So/ following scheme 3/ 4 bratio phenol (compound 20)/ preferably alkyl-substituted in position 3/ alkylate compound 14. The resulting 4-bromophenylacetate close to the ring under the conditions of/ similar-circuit ring compounds 15/ described in reaction scheme 2.

Reaction scheme 3.

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For the introduction of the acetylene group in the molecule carry out the reaction of substituted 6-pratikramana (compound 22) trimethylsilylacetamide and in the presence of copper iodide (I) and an appropriate catalyst, which usually meets the formula Pd(PQ3)2Cl2(Q is phenyl). The reaction is usually carried out in the presence of a catalyst chloride bis(triphenylphosphine)palladium (II), the acid acceptor (such as triethylamine) in an atmosphere of inert gas (argon) by heating in a hermetically sealed tube. Get 6-trimethylsilylamodimethicone shown as compound 23 in figure 3.

6-ethinyl-thiochroman 18 can be used directly in the reaction combinations, as shown in reaction scheme I, or before the combination can be converted into the corresponding zincchloride salt, as described above.

Reaction scheme 4 describes obtaining compounds of formula II, where X is sulfur and at least one of the radicals R4and R5represent lower alkyl, preferably, when both R4and R5represents the lowest alkali, and even more preferably, when R4and R5identical to each other.

Scheme 4

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Following figure 4, 2-substituted, preferably 2,2-disubstituted 6-ethinyl-thiochroman can be obtained in the following way: 4-bromo-thiophenol (compound 20) acelerou using Alliluyeva agent such as acid chloride of acid (compound 24), derived from an appropriately substituted acrylic acid. The acylation is carried out in an inert solvent (such as tetrahydrofuran) in the presence of strong is rooksley group, close to the ring in the presence of a catalyst of the Friedel-(such as aluminised) by stirring in an appropriate solvent, such as dichloromethane. The resulting 2-oxo-6-bromo-thiochroman (compound 26) are usually isolated in crystalline form.

R4and/or R5deputies (both of which cannot be simultaneously hydrogen atoms in the case of the implementation of the process according to scheme 4) and which are preferably identical to each other, for example, both mately, introduced by treating the 2-oxo-6-pratikramana (compound 26) a Grignard reagent, bearing the alkyl substituents R4and R5(such as methylmagnesium, when R4and R5- methyl). Obviously, depending on the molecular ratio of Grignard reagent and oxo-thiochroman (compound 26), and depending on the reaction conditions, the primary reaction products can be those compounds in which either one or both alkyl groups are introduced during the Grignard reaction. When the Grignard reagent, such as methylmagnesium, used in excess, tiraminovogo ring expands and turns of the tertiary alcohol - derived 4-bromo-thiophenol (compound 27).

The ring opening tiofenolov the Lee, is carried out by heating in acidic conditions, preferably by heating compounds 27 in aqueous acid solution. Get 6-pratikraman, which contains the necessary alkyl (or hydrogen) substituents R1, R2, R3, R4and R5shown in the reaction scheme as the connection 28.

6-pratikramana 28 (calthorpe differ at-pratikramana 22 only/ connection 28 in position 2 tiraminovogo ring contains a Deputy) turn 6-(2-trimethylsilyl)- anitelea derived 29/ and then in 6-etinilnoy derived 30 and next/ if you/ in ZnCl salts (31) of the stages of the reactions which are similar to the corresponding stages/ described in connection with reaction scheme 3.

Reaction scheme 5 in General reveals the formation of compounds of formula II in which X is oxygen. Other words/ scheme 6 discloses obtain 2-substituted and preferably 2/2-disubstituted 6-ethnicromanian.

Reaction scheme 5.

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Thus, in accordance with scheme 5 phenol or substituted in the meta position of the phenol by alkylsubstituted (R3) (compound 35) acelerou allermuir reagent such as an acid chloride (compound 24), respectively obtained from si injected with this akrilovogo derivative 24. Acylation with acid chloride 24 preferably carried out in the presence of a strong base (e.g. sodium hydride) in an inert solvent (such as tetrahydrofuran). In reaction scheme 2 as compound 38 shows the resulting substituted phenylacrylate.

Carrying out the reaction of the Friedel-Crafts (catalyst AlCl3inert solvent, such as dichloromethane) of the substituted phenylacrylate 38 receive ring compound, such as 2-oxo-chroman (compound 39), which in position 4 has two R1and R2substituent in position 6 R3- Deputy. Similarly, 2-oxo-thiochroman 26 in figure 4, 2-exogamy 39 scheme 6 is treated with a Grignard reagent to introduce R4and R5substituents. As previously mentioned, in this scheme, R4and R5both cannot be hydrogen atoms, and preferred examples of the implementation of R4and R5are identical, for example both are methyl or ethylpropane. When R4and R5are metelli, as the Grignard reagent is preferably used methylaniline dissolved in tetrahydrofuran (THF). A solution of compound 39 in a suitable solvent, such as anhydrous ser is Amy phenol, containing tertiary alcohol side chain (that is, the molecule in which the disclosed chromanone ring).

The connection 40, which already have the necessary R1, R2, R3, R4and R5the alternate forms in acidic conditions (for example, by heating the aqueous sulfuric acid) kernel, giving chromanone derivative (compound 41). It should be noted that up until this point, the sequence of reactions for the synthesis includes the same or similar stage of obtaining as 2,2-disubstituted derivatives thiochroman (reaction scheme 4), and 2,2-disubstituted derivatives thiochroman (reaction scheme 4), and 2,2-disubstituted derivatives chromane (reaction scheme 5), with the only difference that in scheme 5 original phenolic derivative does not contain halide substituent (such as bromine).

As further disclosed in scheme 5, etinilnoy group is introduced into substituted in position 2 (preferably 2,2-disubstituted) chroman, through a sequence of reactions similar stages of scheme 2 for the introduction of ethyl functions in 4-substituted thiochroman. In accordance with the described method 6-itineray (43) can also be used directly in the reaction combination with coeliadinae formula III are combined in accordance with the proposed method, compounds of formula II, providing biologically active compounds of formula I. the Compound of formula III in themselves are not new and can be obtained by known methods.

In accordance with one preferred embodiment of the proposed synthesis of group a in formula III represents a phenyl group, X1is halogen, preferably bromine or iodine. Ethyl ester of 4-iodobenzoic acid is one of the preferred examples of the reagent of formula III used in combination with compounds of the formula II. Other examples in which A - phenyl, are: ethyl ester of 4-iodophenoxy acid, ethyl ester 4-iodobenzylamine acid, ethyl ester 4-iodine-phenylbutanoate acid, ethyl ester 4-iodine-phenylpentane acid. Can also be used in the proposed method, the reagents in accordance with formula III, in which X1and (CH2)n-B - substituents are in the meta - or ortho-position of the phenyl nucleus.

The compounds of formula III suitable for combination with the compounds of formula II, should be used in light of the proposed synthesis.

When a group of formula III is heteroaryl, at which the notes;

ethyl ester of 2-(2-chloropyrid-5-yl)acetic acid;

ethyl ester of 5-(2-chloropyrid-5-yl)-pentanol acid;

ethyl ester of 2-(2-iodophor-5-yl)acetic acid;

ethyl ester of 5-(2-iodophor-5-yl)pentanol acid;

ethyl ester of 2-(2-iodation-5-yl)acetic acid;

ethyl ester of 5-(2-iodation-5-yl)pentanol acid;

ethyl ester of 5-(3-chloropyridin-6-yl)pentanol acid, and the corresponding chlorine or other halogen-substituted pyrimidinyl or pyrazinyl-analogues of these esters. In this series also In-group of compounds of formula 2 can be protected or unprotected alcohol aldehyde, keto, amide, or other groups mentioned in connection with formula II.

In the scope of the invention also include combinations of compounds of the formula II with compounds of formula III and subsequent implementation of the common operations used in the synthesis, such as locking and unlocking, the FIS official certification, recovery and oxidation, receipt of ester, saponification and the like operations over the resulting molecule (especially the part of it that is derived from a reagent of formula (III), resulting in a gain additional analogs within the scope of formula I and having a roentgen is, what about the need to make the necessary explanations. The combination is usually carried out in the presence of copper iodide (I), a suitable catalyst, typically of the formula Pd(PQ3)2Cl2and acid acceptor, such as triethylamine, by heating in the hermetically sealed tube in an atmosphere of inert gas.

Alternatively, the compound of formula II is first converted into salt (practicelink ZnCl salt to combine. An example of the method of obtaining the ZnCl salts and compounds of formula II (where Z transform of hydrogen in ZnCl), previously described for compound 19.

The combination of ZnCl salts 6-thiochroman, 6-chromanol and 6-(1,2,3,4-tetrahydroquinoline)hatinovich compounds with compounds of the formula III is carried out in the presence of Pd(PQ3)4catalyst (Q is phenyl). In more detail the conditions of the reactions disclosed in the examples of the preparation of specific compounds.

Phenyl-3-methylbut-2-animalfeed (compound 60).

For 2.5 h was heated under reflux the mixture 14,91 g (135,324 mmol) thiophenol and 5.5 g (137,5 mmol) sodium hydroxide in 100 ml of acetone, and then was added dropwise of a solution of 20 g (134,19 mmol) 1-bromo-3-methyl-2-butene in 20 ml of acetone. The resulting solution was boiled under reflux for Ali in the water and was extracted with ethyl ether three times with portions of 50 ml. The ether extracts were combined and washed three times with 30 ml of a 5% sodium hydroxide solution, then with water, a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is then kept in vacuum, and the residue was further purified by distillation with ball reflux (80aboutWith 0.75 ml) to give the target compound as pale yellow oil.

NMR-spectrum (Dl3) of 1.57 (3H, singlet), by 1.68 (3H, singlet), 3,52 (2H, doublet, J 7.7 Hz), from 5.29 (1H, triplet, J 7.7 Hz), 7,14 (1H, triplet, J 7.0 Hz), 7,24 (2H, triplet, J 7.0 Hz), 7,32 (2H, doublet, J 7.0 Hz).

Following the described method and instead of using thiophenol corresponding 3-alkylthiophenes, were obtained the following compounds:

3-were-3-methylbut-2-enersul feed;

3-ethylphenyl-3-methylbut-2-uninsulted;

3-propylphenyl-3-methylbut-2-uninsulted;

3-butylphenyl-3-methylbut-2-uninsulted;

3-pentylphenol-3-methylbut-2-uninsulted;

3-hexylphenyl-3-methylbut-2-uninsulted.

4,4-Dimethylthiochroman (compound 61).

To a solution of 15,48 g (86,824 mmol) phenyl-3-methylbut-2-uninsulted (compound 60) in 160 ml of benzene was sequentially added to 12.6 g (88,767 mmol) of phosphoric anhydride and 11 ml of 85% phosphoric acid. This solution capaticity temperature. Surfaced upper organic layer decantation, and the syrupy residue was extracted three times essential portions of 30 ml of the Organic fractions were combined and washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified by distillation with ball deflector (80aboutWith 0.5 mm RT.cent.), receiving the target compound in the form of blignault oil.

NMR-spectrum (Dl3): 1,30 (6N, singlet), 1,90-1,95 (2H, multiplet), 2,95-of 3.00 (2H, multiplet), of 6.96-7,00 (2H, multiplet),? 7.04 baby mortality-7,07 (1H, multiplet), 7,30-7,33 (1H, multiplet).

This method can be used for obtaining analogs with alkilani in position 7, which is illustrated by the following compounds:

4,4,7-trimethylchitosan (compound 2)

4,4-dimethyl-7-atitikimas

4,4-dimethyl-7-propertyarray

4,4-dimethyl-7-butylthiophene;

4,4-dimethyl-7-hexylthiophene.

4,4-Dimethyl-6-acetylthiocholine (compound 62).

A solution of 14.3 g (80,21 mmol) 4,4-dimethylthiochroman (compound 61) and 6.76 g (86,12 mmol) acetylchloride in 65 ml of benzene was cooled in an ice bath and was added dropwise 26,712 g (102,54 mmol) chloride tin (IV). See what olaney acid and heated under reflux for half an hour. After cooling to room temperature the organic layer was separated, and the aqueous layer was extracted with five 50 ml of benzene. The organic fractions were combined and washed with 5% sodium carbonate, water, saturated sodium chloride solution and then dried over magnesium sulfate. The solvent drove in vacume, and the residue was purified flashgamelicense method (silica gel, 5% ethyl acetate in hexano) followed by distillation with ball reflux (150aboutWith, 0.7 mm RT.cent.), receiving target product as a pale yellow oil.

NMR-spectrum (DCl3): 1,35 (6N, singlet), 1,92-to 1.98 (2H, multiplet), of 2.54 (3H, singlet), 3,02-is 3.08 (2H, multiplet), 7,13 (1H, doublet, J 8.6 Hz), 7,58 (1H, doublet, doublet, J 8.6 Hz, 2 Hz), to 7.99 (1H, doublet, J 2 Hz).

Described is a procedure for acetylation of all compounds that can be obtained by the method described for the synthesis of compound 61.

4,4-Dimethyl-6-utilitiarian (compound 1)

To a solution of 1,441 g (14,2405 mmol) Diisopropylamine in 30 ml of dry tetrahydrofuran in an argon atmosphere at -78aboutWith was added dropwise 9 ml (14.4 mmol) of n-utility in hexane. After stirring this solution at -78aboutWith in an hour was added dropwise a solution of 2.95 and about stirring for one hour at -78aboutThe solution was treated 2,507 g (14,53 mmol) diethylphosphate and brought to room temperature, then was stirred for a 3.75 hours the Solution was transferred into a solution of sitedisability (prepared from 2,882 g (28,481 mmol) Diisopropylamine and 18 ml of 1.6 M (28.8 mmol) of n-utility in hexane) in 60 ml dry tetrahydrofuran at -78aboutWith using dvukhkontsevoi needle. The cooling bath was removed and the solution was stirred at room temperature for 15 h, then extinguished with water and acidified to pH 1 Technomarine hydrochloric acid. The mixture was extracted with five 50 ml of pentane, and the combined organic fractions were washed Technomarine hydrochloric acid, water, saturated sodium bicarbonate solution and saturated saline, then was dried over magnesium sulfate. The solvent was then removed in vacuo, the residue was purified with ball deflector (100aboutWith, 0.7 mm RT.cent.), receiving target product in the form of blignault solid.

NMR-spectrum (DCl3): 1,34 (6N, singlet), 1,94 of 1.99 (2H, multiplet), 3.04 from-is 3.08 (3H, multiplet), 7,06 (1H, doublet, J 8,4 Hz), 7,17 (1H, doublet-doublet, J and 8.4 Hz and 2.1 Hz), 7,51 (1H, doublet, J 2.1 Hz).

Similarly, all of the compounds prepared as well as connect the nCl (compound 63) and ethyl ester of 4-(4,4-dimethylthiochroman-6-yl-ethinyl)benzoic acid (compound 64)

Used reactors, dried in a stove under vacuum, and all operations were carried out in the absence of oxygen in the atmosphere of argon or nitrogen. To a solution of 533,9 mg (2,6389 mmol) 4,4-dimethyl-6-ethinyl-thiochroman (compound I) in 4 ml of anhydrous tetrahydrofuran at 0aboutWith dropwise added 1.7 ml of 1.6 M (2,72 mmol) n-utility in hexane. The reaction mass was stirred at 0aboutC for 10 min and at room temperature for 15 min, re-cooled to 0aboutC and then was treated with a solution of 410 mg (3,005 mmol) of molten zinc chloride in 4 ml of anhydrous tetrahydrofuran, using a needle with two ends. Then the solution was stirred at 0aboutC for 45 min, at room temperature for 20 min and got the connection 63. The product selection was used in subsequent reactions. The solution 724,4 mg (2,6243 mmol) ethyl ester 4-iodobenzoic acid in 4 ml of anhydrous tetrahydrofuran was translating dvukhkontsevoi needle in a suspension of 520 mg (0.45 mmol) tetrakisphosphate in 5 ml of anhydrous tetrahydrofuran and stirred at room temperature for 20 min, then was treated with a solution of alkenylsilanes prepared above, using the introduction dvukhkontsevoi needle. A mixture of peremeshle extraction with three portions of 75 ml of sulphuric ether. The ether extracts were combined and posledovatelno washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified chromatographically (silica gel, 5% ethyl acetate in hexane) and then by liquid chromatography under high pressure (Women Partial M-9 10/50; 4% ethyl acetate in hexane) to give ethyl ester of 4-(4,4-dimethylthiochroman-6-yl-ethinyl)benzoic acid (compound 64) as a colourless oil.

NMR-spectrum (DCl3): of 1.36 (6H), of 1.42 (3H, triplet, J 7 Hz), 1.93 and of 1.99 (2H, multiplet), 3,03-is 3.08 (2H, multiplet), and 4.40 (2H, Quartet, J 7 Hz), to 7.09 (1H, doublet, J 8,4 Hz), 7,22 (1H, doublet, doublet, J 7.8 Hz), of 8.04 (2H, doublet, J 7.8 Hz).

(3-Methyl-4-bromo-phenyl)-3-methylbut-2-uninsulted (compound 65)

To mix the solution 9,52 g (68 mmol) of 3-methyl-4-bromothiophene in 80 ml of acetone was added 2.86 g (68 mmol) poroshkovanii of sodium hydroxide, and the mixture was stirred until complete dissolution. Then the reaction mixture was heated under reflux and then treated with a solution of 11.26 g (68 mmol) of 4-bromo-2-methyl-2-butene in 20 ml of acetone. The mixture was heated under reflux for 0.5 h, cooled to room temperature, the tracts were combined and then washed with water and saturated sodium chloride solution and then dried over magnesium sulfate.

The solvent is kept in vacuum, and the residue was subjected to distillation with ball reflux (140-145aboutC, 0.2 mm RT.cent.), receiving target product as a colorless oil.

NMR-spectrum (DCl3): was 1.58 (3H, singlet), to 1.70 (3H, singlet), of 2.33 (3H, singlet), 3,49 (2H, doublet, J 7.8 Hz), 5,26 (1H, triplet, J 7.8 Hz), 6,98 (1H, doublet, doublet, J 8,3 Hz, 2.3 Hz), 7,17 (1H, doublet, J 2.3 Hz), 7,38 (1H, doublet, J 8,3 Hz).

4,4,7-Trimethyl-6-pratikraman (compound 66).

To 40 grams of vigorously stirred mixture of 10% aqueous phosphoric anhydride in methansulfonate was slowly added 6.0 g (28.8 mmol) of (3-methyl-4-bromophenyl)-3-methylbut-2-uninsulted (compound 65). The mixture was stirred at room temperature for 2 h and then poured into ice. The mixture was extracted twice with pistons ethyl ether in 40 ml each and the combined ethereal extracts are then washed with water and saturated sodium chloride solution and then dried. The solvent is kept in vacuum, and the residue was subjected to distillation with ball reflux at 130aboutWith and 0.07 mm RT.article receiving the target compound in the form of a viscous oil.

The NMR spectrum (CDCl3): 1,28 (6N, singlet), 1,84-of 1.93 (2H, multiplet), and 2.26 (3H, singlet), 2,95-3,03 (2H, multiplet), 6,94 (1H, singlet), 7,46 (1H, single,7-trimethyl-6-pratikraman (compound 66), 314 mg (3.2 mmol) of trimethylsilylacetamide, 40 mg (0.21 mmol) of copper iodide (I), 80 mg (0.11 mmol) chloride bis (triphenylphosphine) palladium (II) and 1 ml of triethylamine was degirolami in the atmosphere of nitrogen and heated in a sealed tube at 85aboutWith over 15 hours the Mixture is then further processed 20 mg (0.11 mmol) of copper iodide (I) and 40 mg (0.06 mmol) of palladium (II) catalyst. Then the mixture was heated in a nitrogen atmosphere in a sealed tube at 100aboutC for 64 hours, the Triethylamine drove in a vacuum, and the residue was purified chromatographically on silica gel by elution of hexane, obtaining the target product as a yellow oil.

The NMR spectrum (CDCl3): 0,28 (N, singlet), 1,30 (6N, singlet), 1,88-of 1.97 (2H, multiplet), of 2.33 (3H, singlet), 2,97 was 3.05 (2H, multiplet), 6,92 (1H, singlet), the 7.43 (1H, singlet).

4,4,7-Trimethyl-6-utilitiarian (compound 2)

A mixture of 380 mg (1,69 mmol) trimethylsilyl-(4,4,7-trimethylchitosan-6-yl)aceti-Lena. Connection 67, 4 ml of isopropanol and 2.5 ml of water odnopolyarnogo caustic potash was degirolami in nitrogen atmosphere and stirred at room temperature for 16 hours the Mixture was concentrated under vacuum and was extracted with two portions of sulphuric ether (10 ml each). The ether extracts were combined and the follower is thenali in vacuum, receiving the target compound as a yellow oil.

NMR-spectrum (DCl3): of 1.31 (6H, singlet), 1,88 is 1.96 (2H, multiplet), to 2.35 (3H, singlet), 3,00-is 3.08 (2H, multiplet) at 3.25 (1H, singlet), 6,94 (1H, singlet), 7,47 (1H, singlet).

S-(4-bromophenyl)new ether 3,3-dimethylthiazol acid (compound 69)

To a cooled in an ice bath to a solution of 1.92 g (80 mmol) of sodium hydride prepared from 60% suspension in mineral oil by washing CH ml of hexane, 30 ml of anhydrous tetrahydrofuran was slowly added in an argon atmosphere a solution of 15.1 g (80 mmol) of 4-bromothiophene in 60 ml of anhydrous tetrahydrofuran for 1 h the Mixture was stirred at 0aboutWith in the next 30 min and then treated with a solution of 10.1 g (85 mmol) of dimethylacrylamide in 30 ml of anhydrous tetrahydrofuran. The cooling bath was then removed, and the mixture was stirred at room temperature for 40 hours, the Reaction mixture was poured into 200 ml of water containing 2 ml of glacial acetic acid, and the organic layer was separated. This organic layer was washed twice with water (portions 75 ml) and then dried over magnesium sulfate. The solvent is kept in vacuum, obtaining the target compound as a yellow oil.

The NMR spectrum (CDCl3): 1,91 (3H, Singh is m-2-oxo-thiochroman (compound 70).

To stir cooled ice suspension of 15.9 g (119 mmol) of aluminofluoride in 140 ml of dichloromethane was added under nitrogen atmosphere a solution of 21,64 g (79,9 mmol) S-(4-bromophenyl)new ether 3,3-dimethylthiazol acid (compound 69) in 100 ml of dichloromethane. The mixture was then stirred at room temperature for 72 h and then poured into 250 g of ice and brine. The mixture was extracted with dichloromethane, and the combined organic extracts were washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was subjected to recrystallization from hexanol, obtaining the target compound as white crystals.

NMR-spectrum (DCl3): 1,40 (6N, singlet), to 2.67 (2H, singlet), 7,31-7,40 (3H, multiplet);

Mass spectrum m/e 269,9714 (calculated value for C11H11SOBr equal 269,9714).

4-Bromo-2-(1,1,3-trimethyl-3-oxobutyl)-thiophenol (compound 71).

To 3,49 g (32,8 mmol) of lithium perchlorate in an atmosphere of argon was added 35 ml of 3.0 M (105 mmol) Metalmania bromide in sulphuric ether. The resulting mixture is added dropwise with stirring, treated with a solution of at 2,961 g (10,926 mmol) 4,4-dimethyl-6-bromo-2-oxo-thiochroman (compound 70), and the reaction mixture is then boiled with reverse cold is ml of concentrated sulfuric acid. Separated the organic layer and the aqueous layer was twice extracted with ethyl ether (portions of 25 ml each). The organic layers were combined and successively washed twice with 25 ml saturated sodium bicarbonate solution, 25 ml water and 25 ml of saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified chromatography, obtaining the target product as a yellow oil.

The NMR spectrum (CDCl3): 1,05 (6N, singlet), 1,52 (6N, singlet), 2,30 (2H, singlet), 3,71 (1H, singlet), 7,22 (1H, doublet-doublet, J 8.5 Hz, 2.1 Hz), 7,28 (1H, doublet, J 8.5 Hz), 7,35 (1H, doublet, J 2.1 Hz).

Using ethylmagnesium instead of methylacrylamide get the corresponding 4-bromo-2-(1,1-dimethyl-3-ethyl-3-oxyphenyl)-thiophenol.

2,2,4,4-Tetramethyl-6-pratikraman (compound 72).

A mixture of 500 mg (1,49 mmol) 4-bromo-2-(1,1,3-trimethyl-3-oxobutyl)thiophenol (compound 71) and 8 ml of 20% aqueous sulfuric acid was heated under reflux for 24 hours the Mixture was extracted with hexane, the organic extracts were combined and then washed with water, saturated sodium bicarbonate solution, again with water, saturated sodium chloride solution and then dried over magnesium sulfate. Dissolve the compound in the form of a colorless oil.

The NMR spectrum (CDCl3): 1,35 (6N, singlet), 1,40 (6N, singlet), of 1.93 (2H, singlet), 7,17 (1H, double doublet, J and 8.4 Hz and 2.1 Hz), 7.23 percent (1H, doublet, J 8,4 Hz), 7,26 (1H, doublet, J 2.1 Hz).

Mass spectrum m/e 284,0221 (calculated value for C13H17SBr 284,0234).

2,2,4,4-Tetramethyl-6-trimethylsilyl - ethinyl-thiochroman (compound 73).

A solution of 600 mg (2,11 mmol) of 2,2,4,4-tetramethyl-6-pratikramana (compound 72) in 1.5 ml of triethylamine was placed in a thick-walled tube and degirolami and then treated in an argon atmosphere 1.4 g (of 14.3 mmol) trimethylsilylacetamide and poroshkovanii a mixture of 75 mg (0,39 mmol) of copper iodide (I) and 150 mg (0.21 mmol) chloride bis(triphenylphosphine)palladium (II). The reaction mixture was again degirolami, then placed in an atmosphere of argon, and the tube was sealed. The mixture was heated at 100aboutC for 24 h, allowed it to cool to room temperature and then was treated with additional 1.4 g (of 14.3 mmol) trimethylsilylacetamide and poroshkovanii a mixture of 75 mg (0,39 mmol) of copper iodide (I) and 150 mg (0.21 mmol) chloride bis(triphenylphosphine)palladium (II). The mixture was degirolami, was placed in an atmosphere of argon and then was kept in a sealed tube at 100aboutC for 96 hours the Mixture was cooled to room temperature and was extracted with tried the water and 25 ml of a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was subjected to purification by means of flash chromatography on silica gel using as eluting solvent hexane, and then 3% solution of ethyl acetate in hexano. The result has been the target compound as a yellow crystalline substance.

NMR-spectrum (DCl3): 0,23 (N, singlet), 1,36 (6N, singlet), 1,39 (6N, singlet), was 1.94 (2H, singlet), 7,17 (1H, double doublet, J 8.2 Hz, 1.8 Hz), 7,2 (1H, doublet, J 1.8 Hz), 7,30 (1H, doublet, J 8.2 Hz).

Mass spectrum m/e 302,1519 (calculated for C18H26SSi 382,1524).

2,2,4,4-Tetramethyl-6-utilitiarian (compound 3).

To a solution of 527,6 mg (1,75 mmol) of 2,2,4,4-tetramethyl-6-trimethylsilyl-tinytiger Mans (compound 73) in 4 ml isopropanol in an atmosphere of argon was added 4 ml odnopolyarnogo solution of caustic potash. The reaction mixture was stirred at room temperature for 20 h, and isopropanol then drove in a vacuum. The residue was extracted with ethyl ether and the combined ethereal extracts are then washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is kept in vacuum, obtaining the target compound as a yellow oil.

NMR-spectrum (DCl3): 1,34 (6 is C), 7,30 (1H, doublet, J 8.1 Hz).

Mass spectrum m/e 230,1122 (calculated for C15H18S 230,1129).

Diphenyl-3-methyl-3-butene-1-infostat (compound 75).

To a cooled with ice to a solution of 12.2 g (141,65 mmol) 3-methyl-3-butene-1-ol (Aldrich) and 11.9 g (150,44 mmol) of pyridine in 100 ml of tetrahydrofuran was added dropwise in an argon atmosphere a solution of 38.5 g (143,21 mmol) diphenylchlorophosphine (compound 32) in 100 ml of tetrahydrofuran. The mixture was boiled under reflux for three hours, then cooled and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in 400 ml of a mixture of sulphuric ether and hexane (1:1) and then washed with water h ml, 75 ml saturated sodium chloride solution and dried over magnesium sulfate. The solvent is kept in vacuum, obtaining the target compound as pale yellow oil.

NMR-spectrum (DCl3): 1,69 (3H, singlet), is 2.37 (2H, triplet, J 7 Hz), 4,32 (2H, Quartet, J 7 Hz), 4.72 in (1H, singlet), 4,80 (1H, 7,10-TO 7.35 (10H, multiplet).

4,4-DIMETHYLPROPANE (compound 76).

In the dry, cooled by ice flask containing 34,95 g (0,134 mol) chloride tin (IV) was rapidly added in an argon atmosphere 63,0 g (0,669 mol) of phenol. The mixture was stirred at 0aboutWith in half an hour and then were treated to 43.0 g (0, amasyali at room temperature for 21 h and then was suppressed by infusion of 700 g of ice and 1 l of 1.5 N. caustic soda. The mixture was extracted with CH ml and CH ml of sulphuric ether. United ether fractions were washed dwuhmomentnam sodium hydroxide, saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified using flash chromatography on silica gel, elwira 2% ethyl ether in hexane and obtaining the target compound as a colourless oil.

NMR-spectrum (DCl3): 1,34 (6N), 1,80-1,85 (2H, multiplet), 4,15-4,20 (2H, multiplet), to 6.80 (1H, double doublet, J 8.1 Hz, 1.5 Hz), 6.87 in (1H, triplet-doublet, J 8.1 Hz, 1.5 Hz), 7,07 (1H, triplet-doublet, J 8.1 Hz, 1.5 Hz), 7,26 (1H, double doublet, J 8.1 Hz, 1.5 Hz).

In the same manner but using the corresponding 3-alkyl phenol instead of phenol, obtained the following compounds: 4,4,7-trimethylpropane; 4,4-dimethyl-7-Edilkamin; 4,4-dimethyl-7-propylparaben; 4,4-dimethyl-7-Pantilimon.

4,4-Dimethyl-6-acetylcholin (compound 77).

To mix the solution 7,94 g (48,9425 mmol) 4,4-DIMETHYLPROPANE (compound 76) in 70 ml of nitromethane was added in an argon atmosphere 4.0 g (50,96 mmol) acetylchloride, and then 6.8 g (51 mmol) of aluminium chloride. This mixture was stirred at room temperature for 5.5 h and then cooled in an ice bath and treated slow relatively 100 ml of sulphuric ether. The organic layer was separated, washed with water, saturated solution of sodium bicarbonate and sodium chloride and dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was subjected to purification by means of flash chromatography on silica gel, elwira 10% ethyl acetate in hexano. The product was subjected to distillation on ball dephlegmator (95-100aboutC, 0.15 mm RT.cent.), receiving the target compound as a colourless oil.

The NMR spectrum (CDCl3): 1,40 (6N), 1,95-2,00 (2H, multiplet), 2,58 (3H), 4,25-4,30 (2H, multiplet), 6,83 (1H, doublet, J 8.0 Hz), a 7.62 (1H, double doublet, J 8.0 Hz, 1.5 Hz), 8,00 (1H, doublet, J 1.5 Hz).

Similarly turned other chromanone compounds are obtained analogously to compound 76 in their respective acetyl analogues.

4,4-Dimethyl-6-itineray (compound 4).

To a solution 2,47 g (24,41 mmol) Diisopropylamine in 40 ml of anhydrous tetrahydrofuran in an argon atmosphere at -78aboutWith was added dropwise to 15.2 ml, 1.6 M (24,32 mmol) n-utility in hexane. The mixture was stirred at -78aboutC for one hour and then was added dropwise a solution to 4.98 g (24,38 mmol) 4,4-dimethyl-acetylcholine (compound 77) in 1 ml anhydrous tetrahydrofuran. After stirring at -78aboutFrom within the camping was stirred at room temperature for a period of 2.75 hours The solution is then translated using dvukhkontsevoi needle into a solution of sitedisability made from of 4.95 g (48,92 mmol) Diisopropylamine and 30.5 ml of 1.6 M (48.8 mmol) of n-utility in hexane, 80 ml of anhydrous tetrahydrofuran at -78aboutC. the Cooling bath was removed and the mixture was stirred at room temperature for 18 h and then extinguished 50 ml and 25 ml Technomarine hydrochloric acid. The mixture was extracted with 100 ml and three times with 50 ml of pentane and the combined organic extracts were washed Technomarine hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is then kept in vacuum and the residue was purified using flash chromatography on silica gel by elution 10% ethyl acetate in hexane and distilled with ball reflux (70aboutC, 0.35 mm RT.cent.). Received target compound as a colourless crystalline solid.

The NMR spectrum (CDCl3): 1,33 (6N), 1,81 IS 1.86 (2H, multiplet), of 3.00 (1H, singlet), 4,19-4,24 (2H, multiplet), to 6.75 (1H, doublet, J 8.5 Hz), 7,22 (1H, double doublet, J 8.5 Hz, 2.3 Hz), 7,44 (1H, doublet, J 2.3 Hz).

Following the same method, acetyl derivatives prepared in the same period the initial ester of 4-(4,4-DIMETHYLPROPANE-6-yl-ethinyl)benzoic acid (compound 80).

Used reactors were dried over burner in a vacuum and all subsequent procedures were carried out without oxygen in the atmosphere of nitrogen or argon. To a solution of 509,4 mg (2,74 mmol) 4,4-dimethyl-6-itinirary (compound 78) in 4 ml of anhydrous tetrahydrofuran at 0aboutWith was added dropwise 1,72 ml of 1.6 M to 2.75 mmole) n-utility in hexane. Stirring was started at 0aboutC for 30 min and kept at room temperature for 15 min, after which the solution was again cooled to 0aboutC and then was treated with a solution of 380 mg (2,79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran, using dvukhkontsevoi needle. The resulting solution was stirred at 0aboutC for one hour and then for 15 min at room temperature, receiving a connection 79.

The obtained product without allocation used in the following way. The solution 628,6 mg (2,74 mmol) ethyl ester 4-bromobenzoyl acid in 4 ml of anhydrous tetrahydrofuran translated using dvukhkontsevoi needle in a suspension of 380 mg (0.33 mmol) tetranitroaniline in 5 ml of anhydrous tetrahydrofuran and stirred at room temperature for 15 min, and then were processed using dvukhkontsevoi needle solution alkenylsilanes, the sentence is malnoy hydrochloric acid. The mixture then was extracted three times with 75 ml of ethyl ether, and the ether extracts were combined and sequentially washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was further purified using flash chromatography on silica gel with elution 10% ethyl acetate in hexane. Got a white solid product (compound 80).

The NMR spectrum (CDCl3):1,36 (6N), OF 1.42 (3H, triplet, J and 7.3 Hz), 1,82 is 1.86 (2H, multiplet), 4,21-of 4.25 (2H, multiplet), and 4.40 (2H, Quartet, J and 7.3 Hz), 6,79 (1H, doublet, J 8.1 Hz), 7,28 (1H, 7,58 (2H, doublet, J 8.7 Hz), 8,03 (2H, doublet, J 8.7 Hz).

Phenyl ether 3,3-dimethylacrylic acid (compound 81).

To a cooled in an ice bath to a solution of 1.29 g (54 mmol) of sodium hydride prepared from 60% suspension in mineral oil three times washing with hexane (three times 10 ml), 20 ml of anhydrous tetrahydrofuran was slowly added in the presence of oxygen a solution of 5 g (53 mmol) of phenol in 50 ml of anhydrous tetrahydrofuran. The mixture was treated with a solution of 7 g (59 mmol) dimethylacrylamide in 30 ml of anhydrous tetrahydrofuran. The cooling bath was then removed and the mixture was stirred for follow the 150 ml of sulphuric ether and the ether extract was washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was purified flash chromatography on silica gel by elution with 5% sulphuric ether in hexano. Received target compound as a yellow oil.

NMR-spectrum (DCl3): 1,99 (3H, singlet), 2,24 (3H, singlet), to 5.93 (1H, broad singlet), 7,10 (2H, triplet, J 7.8 Hz).

4,4-Dimethyl-2-oxo-chroman (compound 82).

To stir cooled in an ice bath) suspension of 10.4 g (78 mmol) of aluminofluoride in 160 ml of dichloromethane was slowly added in an argon atmosphere a solution of 7 g (39.8 mmol) of phenyl ether 3,3-dimethylacrylic acid (compound 81) in 40 ml of dichloromethane. The cooling bath was removed and the mixture was stirred for a further 42 hours the Mixture was poured into a mixture of ice and brine, and separated the organic layer. The aqueous layer was extracted with dichloromethane, the organic extracts were combined and washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified using flash chromatography on silica gel using 10% sulfuric ether in hexane. Received target product as a colorless oil.

NMR-spectrum (DCl3): 1,30 (6N, singlet), of 2.56 (2H, singlet, 7,06 (1H, DV. doublet, J 8.0 Hz, 1.4 Hz), mass-spectrum m/e 176,0852 (calculated for C11H12ABOUT2176,0837).

2-(1,1,1-Trimethyl-3-oxobutyl)phenol (compound 83).

To 11 ml of 3.0 M (33 mmol) of methylmagnesium in tetrahydrofuran, cooled in an ice bath, was added in nitrogen atmosphere the solution to 1.96 g of 4,4-dimethyl-2-oxo-chroman (compound 82) in 35 ml of anhydrous sulphuric ether. Then the cooling bath was removed and the mixture was stirred at room temperature for 72 h, the Reaction mixture was poured into a mixture of 100 g of ice in 3 ml of concentrated sulfuric acid and stirred until dissolution of the magnesium salts. Separated the organic layer and the aqueous layer was extracted with twice 50 ml of ethyl ether. The organic layers were combined and sequentially washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified using flash chromatography on silica gel by elution 20% ethyl acetate in hexane. Received target compound as a pale yellow solid product.

NMR-spectrum (DCl3):1,13 (6N, (C), 1,48 (6N, (C), 1,89 (1H, s) of 2.23 (2H, s), 6,60 (1H, DV.d, J 7.9 Hz, 1.4 Hz), 6,83 (1H, s), at 6.84 (1H, Tr.D. J 7.9 Hz, 1.4 Hz), 7,07 (1H, Tr.D. J 7.9 Hz, 1.6 Hz), 7,31 (1H, DV.D. J 7.9 Hz, 1.6 Hz).

Mass-sper CLASS="ptx2">

Under reflux in nitrogen atmosphere for 4 h and boil the mixture 2,98 g (of 14.3 mmol) of 2-(1,1,3-trimethyl-3-oxobutyl)phenol (compound 83) and 40 ml of 20% aqueous sulfuric acid. The mixture was then stirred at room temperature for 72 h and was diluted with 50 ml water. The mixture was extracted with three 20 ml portions of hexanol. The organic extracts were combined and then washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then kept in vacuum, obtaining the target compound as a colourless oil.

NMR-spectrum (DCl3):1,36 (6N, C) 1,37 (6N,) and 1.83 (2H, s) of 6.71 (1H, DV.D. J 8.2 Hz, 1.5 Hz), 6,92 (1H, Tr.D. J 8.2 Hz, 1.5 Hz), to 7.09 (1H, Tr.D. J 8.2 Hz, 1.5 Hz), 7,29 (1H, DV.D. J 8.2 Hz, 1.5 Hz).

2,2,4,4-Tetramethyl-6-acetylcholin (compound 85).

It chilled in an ice bath to a solution of 2 g (10,53 mmol) of 2,2,4,4-tetramethylchroman (compound 84) in 25 ml of nitromethane was added in nitrogen atmosphere 941 mg (11,99 mmol) acetylchloride and then 1,59 g (11,92 mmol) aluminofluoride. The cooling bath was removed and the mixture was stirred at room temperature for 16 hours the Mixture was again cooled in an ice bath and was treated with 25 ml of concentrated hydrochloric acid. Then the mixture was filtered, and the residue was washed on the silica gel, using for elution of 10% ethyl acetate in hexano. Received target product as a yellow oil.

NMR-spectrum (DCl3):1,38 (6N, s), 1.39 in (6N, C) to 1.87 (2H, s), of 2.56 (3H, s), 6,83 (1H, d,J 8.7 Hz), 7,71 (1H, DV.d, J 8.7 Hz and 2.1 Hz), 7,98 (1H, d, 2.1 Hz).

Mass spectrum m/e 232,1468 (calculated for C13H20ABOUT2232,1464).

2,2,4,4-Tetramethyl-6-itineray (compound 5).

To a cooled (-78aboutC) a solution of 522 mg (5.17 mmol) of Diisopropylamine in 8 ml of anhydrous tetrahydrofuran (THF) slowly under nitrogen atmosphere was added 3,23 ml of 1.6 M (5.17 mmol) of n-utility in hexane. The mixture was stirred at -78aboutC for 40 min and then treated with a solution of 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylcholine (compound 85) in 2 ml of anhydrous tetrahydrofuran. The mixture was stirred at -78aboutWith in the next hour and then added 895 mg (5,19 mmol) diethylphosphate. The reaction mixture was allowed to take room temperature and transferred needle with two ends in the solution diisopropylamide lithium in tetrahydrofuran at -78aboutWith, prepared as described above from 1.04 g (10,34 mmol) Diisopropylamine and 6,46 ml of 1.6 M (10,34 mmol) n-utility in hexane. The cooling bath was removed and the mixture was stirred at room Tempe is delali the organic layer, the aqueous layer was extracted three times with 30 ml of pentane. The organic extracts were combined and then washed 2,30 ml of diluted hydrochloric acid, water, three times with 30 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified flash chromatography on silica gel using as eluting solvent 2% ethyl acetate in hexane. Received target compound as pale yellow oil.

NMR-spectrum (DCl3): 1,31 (6N, singlet), 1,32 (6N, singlet), 1,50 (2H, singlet), of 3.00 (1H, singlet), 6,72 (1H, doublet, J 8,4 Hz), 7,20 (1H, DV. doublet, J and 8.4 Hz and 2.1 Hz), 7,42 (1H, doublet, J 2.1 Hz).

Mass spectrum m/e 214,1251 (calculated for C15H18About 214,1357).

3-Methyl-phenyl-3,3-dimethylacrylate (compound 87).

60% suspension of sodium hydride 3,22 g (81 mmol) in mineral oil was washed with hexane three times (10 ml) and then was treated with 30 ml of anhydrous tetrahydrofuran. The mixture was cooled in an ice bath and then treated with a solution of 8.6 g (79.5 mmol) of m-cresol in 80 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred for 10 min and then treated with a solution of 10.5 g (88,5 mmol) dimethyloctyl and then was poured into a mixture of 150 ml of water and 1 ml of glacial acetic acid. The mixture was stirred 10 min, and separated the organic layer. The aqueous layer was extracted with ethyl ether twice with portions of 50 ml Organic layers were combined and sequentially washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified flash chromatography on silica gel with 10% ethyl acetate in hexane. Received target compound as pale yellow oil.

The NMR spectrum (CDCl3): 1,95 (3H, d, J 1.3 Hz), of 2.21 (3H, d, J 1.2 Hz), was 2.34 (3H, s), 5,90 (1H, Shir. 6,86-6,93 (2H, m), 7,01 (1H, d, J 8.2 Hz), 7,24 (1H, triplet, J 7.2 Hz).

2-(1,1,3-Trimethyl-3-oxobutyl)-5-methyl-phenol (compound 88).

To a suspension of 13 g (97.5 mmol) of aluminofluoride in 200 ml of methylene chloride in 200 ml of methylene chloride, cooled in an ice bath, was added dropwise in an argon atmosphere a solution of 9.0 g (to 47.4 mmol) 3-methyl-phenyl-3,3-dimethylacrylate (compound 87) in 100 ml of dichloromethane. The reaction mixture was stirred at 0aboutWith in the next 30 min and then at room temperature for 15 hours, the Reaction mixture was poured into 200 ml of a mixture of ice water and salt, the organic layer was separated, and the aqueous layer was extracted with ethyl ether (50 ml). The organic layers were combined and sequentially washed in the Ali purification using flash chromatography on silica gel, using 5% ethyl acetate with hexane. Received a mixture of isomeric products with a ratio of 4,4,7-trimethyl-2-oxo-chroman and 4,4,5-trimethyl-2-oxo-chroman about 2.5:1 in the form of a pale yellow oil. To a solution of 3.8 g (20 mmol) of this mixture of isomeric 2-oxo-chroman in 60 ml of sulphuric ether at 0aboutWith added in an argon atmosphere, 20 ml, 3.0 M (60 mmol) of methylacrylamide in sulphuric ether. The reaction mixture was stirred at room temperature for 48 h and then was poured into a mixture of ice and 1 ml of concentrated sulfuric acid. The organic layer was separated and the aqueous layer was extracted with ethyl ether twice with portions of 50 ml Organic layers were combined and sequentially washed with water, saturated sodium bicarbonate solution, again with water and then a saturated solution of sodium chloride in vacuo, and the residue was purified using flash chromatography on silica gel using a mixture of 15% ethyl acetate with hexane. Received target compound as a colourless oil.

NMR-spectrum (DCl3):1,14 (6N, (C), 1,45 (6N, (C), are 2.19 (3H, s), of 2.21 (2H, s), to 6.39 (1H, d, J 1.8 Hz), to 6.67 (1H, DV.D. J 7.9 Hz, 1.8 Hz), 7,16 (1H, d, J 7.9 Hz), 7,44 (1H, s).

2,2,4,4,7-Pentamethylchroman (compound 89).

To 2.16 g (11.7 mmol) of 2-(1,1,3-trimethyl-3-oxobutyl)-5-METHYLPHENOL (compound 88) was added to the group of 13 h and then cooled. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic extracts were combined and washed successively with water, saturated sodium bicarbonate solution, again with water and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum, obtaining the target compound as a yellow oil.

AMP-spectrum (CDCl3): 1,32 (6N, singlet), 1,34 (6N, singlet), is 1.81 (2H, singlet), and 2.26 (3H, singlet), 6,63 (1H, singlet), 6,72 (1H, doublet, J 7.9 Hz), to 7.15 (1H, doublet, J 7.9 Hz).

To a cooled in an ice bath, the solution to 1.96 g (9.6 mol) 2,2,4,4,7-pentamethyl-chroman (compound 89) in 30 ml of nitromethane was added in an argon atmosphere 1,059 g (13.5 mmol) of acetylchloride, and then 1.9 grams (to 14.3 mmol) aluminofluoride. The reaction mixture was stirred at room temperature for 14 h and then cooled in an ice bath and was treated with 25 ml of concentrated hydrochloric kislota. The mixture was heated at room temperature and diluted with ethyl ether and water. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic extracts were combined and then washed with water, saturated sodium bicarbonate solution, again with water and a saturated solution of poweranimator on silica gel, using for elution of a mixture of 5% ethyl acetate and hexanol. Received target compound as pale-yellow oil.

The NMR spectrum (CDCl3): 1,36 (6N, singlet), 1,37 (6N, singlet), to 1.86 (2H, singlet), 2,49 (3H, singlet), of 2.56 (3H, singlet), of 6.65 (1H, singlet), 7,74 (1H, singlet).

2,2,4,4,7-Pentamethyl-6-tiny-chroman (compound 9).

To a solution of 455 g (4.5 mmol) of Diisopropylamine in 5 ml of anhydrous tetrahydrofuran at -78aboutC in argon atmosphere dobavlyali 3 ml of 1.5 M n-utility in hexane. The mixture was stirred at -78aboutWith in the next 45 min and then treated with a solution of 1.07 g (4.3 mmol) 2,2,4,4,7-pentamethyl-6-acetyl-chroman (compound 90) in 4 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at -78aboutC for one hour and then treated 776 mg (4.5 mmol) of diethyl ether chlorophosphate. The mixture was given the opportunity to spontaneously take room temperature and then translated dvukhkontsevoi needle into a solution of sitedisability in 10 ml of anhydrous tetrahydrofuran at -78aboutWith that received in accordance with the method above, using 910 mg (9.0 mmol) of Diisopropylamine and 6 ml of 1.5 M (9.0 mmol) of n-utility in hexane. The mixture was stirred at room temperature for 15 h and the second layer, and the aqueous layer was extracted with pentane. The organic extracts were combined and then washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified by distillation with ball reflux (82aboutC, 0.3 mm RT. Art.), obtaining the target compound as pale yellow oil.

The NMR spectrum (CDCl3): 1,32 (6N, singlet), 1,34 (6N, singlet), is 1.81 (2H, singlet), a 2.36 (3H, singlet), 3,18 (1H, singlet), only 6.64 (1H, singlet), 7,40 (1H, singlet).

Mass spectrum m/e 228,1520 (calculated for C16H20About 228,1514).

N-(4-bromophenyl)-3,3-dimethylacrylic - MFA (compound 92).

To a solution 9,48 g (80 mmol) of 3,3-dimethylacrylamide in 200 ml of anhydrous tetrahydrofuran with vigorous shaking solution was added 13,76 g (80 mmol) of 4-bromoaniline in 300 ml of anhydrous tetrahydrofuran. The mixture was left at room temperature for two hours and then was treated with 80 g of ice, and then 200 ml of hexane. Separated the organic layer and the aqueous layer was extracted with hexane twice with portions of 50 ml Organic layers were combined and sequentially washed with water (30 ml) and saturated sodium chloride solution, twice paracrystalline from a mixture of ethyl acetate and hexanol, receiving colorless crystals of the target compound.

The NMR spectrum (CDCl3): 1,91 (3H, singlet), of 2.23 (3H, singlet), 5,73 (1H, broad singlet), 7,38-of 7.55 (5H, multiplet).

4,4-Dimethyl-6-bromo-2-oxo-1,2,3,4-tet - rehydrogenation (compound 93).

Within 25 min to 6.7 g (to 26.02 mmol) of molten N-(4-bromophenyl)-3,3-dimethylacrylamide (compound 92), heated to 135aboutWith added 4.15 g (31,09 mmol) aluminofluoride. The reaction mixture was stirred at 130aboutC for 16 h and then extinguished was treated with additional 1 g (7.5 mmol) of aluminofluoride. The reaction mixture was stirred at 130aboutWith in the next 9 hours and then cooled to room temperature. The reaction mixture was then extinguished by slow addition of 100 ml of ice water at low heat bulb to enhance mixing. The mixture was extracted with ethyl ether, once with 100 ml and four portions of 50 ml. Organic extracts were combined and washed with 25 ml saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified using flash chromatography on silica gel using 30% ethyl acetate with hexane. Got a pale yellow solid target product.

NMR-spectrum ( J 2.1 Hz), 10,12 (1H, broad singlet).

4,4-Dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline (compound 94).

Using dvukhkontsevoi needle to 23,5 ml of 1.0 M (23.5 mmol) of almoguera lithium in tetrahydrofuran, heated to the boil under reflux, under nitrogen atmosphere was added a solution of 4.95 g (19,48 mmol) 4,4-dimethyl-6-bromo-2-oxo-1,2,3,4-then it is carbonated - drainline (compound 93) in 50 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous sulphuric ether. The mixture was boiled under reflux for two hours and then cooled to room temperature. The reaction mixture was then extinguished by slow addition of 25 ml of water and then 50 ml of 5% sodium hydroxide solution. The mixture was extracted with ethyl ether twice in portions of 25 ml, the organic extracts were combined and then washed with 25 ml water and 25 ml of saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified using flash chromatography on silica gel using 15% ethyl acetate in hexano. Got a brown oily target connection.

The NMR spectrum (CDCl3): of 1.27 (6H, singlet), 1,67-of 1.74 (2H, multiplet), 3,23-of 3.32 (2H, multiplet), 3,90 (1H, broad singlet), 6,33 (1H, doublet, J 8,4 Hz), 7,10 (1H, doublet-doublet, J 8,4 Hz, 2.3 Hz), 7,25 (

In a thick-walled tube was degirolami under argon a solution of 1,608 g (6.7 mmol) of 4,4-dimethyl-6-bromo-1,2,3,4-tetrahydroquinolin - on (compound 94) in 1.5 ml of triethylamine and then was treated with 75 mg (0,39 mmol) of copper iodide (I) and 150 mg (0.21 mmol) chloride bis (triphenylphosphine) palladium (II). The mixture was again degirolami under argon, was treated 2,09 g (of 21.2 mmol) trimethylsilylacetamide and the tube was sealed. The mixture was heated at 50aboutWith in 48 hours After cooling to room temperature, to the reaction mixture were added methylene chloride and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified using flash chromatography on silica gel using 10% ethyl acetate in hexano. Received a yellow oily target product.

The NMR spectrum (CDCl3): 0,20 (N, singlet), 1,20 (6N, singlet), 1,57-to 1.63 (2H, multiplet), 3,16-of 3.25 (2H, multiplet), was 4.02 (1H, broad singlet), 6,24 (1H, doublet, J 8.2 Hz), 7,00 (1H, doublet-doublet), J 8.2 Hz and 1.8 Hz), 7,26 (1H, doublet, J 1.8 Hz).

4,4-Dimethyl-6-ethinyl-1,2,3,4-tetrahed - rhinolin (compound 6).

To a solution of 569 mg (2.21 mmol) of 4,4-dimethyl-6-trimethylsilylethynyl-1,2,3,4-Tetra - hydroidolina (compound 95) in 3 ml of isopropanol was added in an argon atmosphere 1 ml odnopolyarnogo aqueous solution of caustic potassium. The reactions which were strayaway ethyl ether, the ethereal extracts are then washed with water and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was purified using flash chromatography on silica gel using a mixture of 10% ethyl acetate with hexane. Got a brown oily target connection.

Etilogy ether of 6-chloronicotinic acid (compound 98).

A mixture of 15.75 g (0.1 mmol) of 6-chloronicotinic acid and 6.9 g (0.15 mmol) of ethanol, an increase of 22.7 g (0.1 mmol) dicyclohexylcarbodiimide and 3.7 g of dimethylaminopyridine in 200 ml of dichloromethane was heated under reflux for two hours. The mixture was allowed to cool, the solvent is kept in vacuum and the residue was subjected to flash chromatographic purification, obtaining the target compound in the form of a white solid with a low melting point.

The NMR spectrum (CDCl3):the 1.44 (3H, triplet, J 6.2 Hz), of 4.44 (2H, Quartet, J 4.4 Hz), 7,44 (1H, doublet, J 8.1 Hz), of 8.27 (1H, doublet-doublet, J 8.1 Hz, 3 Hz), of 9.02 (1H, doublet, J 3 Hz).

The described procedure can be used for the esterification of any of the other halogen-substituted acids used in the preparation of these compounds, such as etilogy ether 2-(2-chloropyrid-5-yl) acetic acid, ethyl ester 5-(2-harpies acid, ethyl ester of 2-(2-iodation-5-yl) acetic acid, ethyl ester 5-(2-iodation-5-yl)pentanol acid, ethyl 2-(3-chloropyridin-6-yl)acetic acid, ethyl ester 5-(3-chloropyridin-6-yl)pentanol acid, and the corresponding chlorine or other halides substituted pyrimidinyl or pyrazinyl-analogues of such esters.

The NMR spectrum (CDCl3): 1,26 (6N, singlet), 1,65-1,72 (2H, multiplet), 2,96 (1H, singlet), 3.27 to to 3.34 (2H, multiplet), 6,34 (1H, doublet, J 8,3 Hz), was 7.08 (1H, doublet-doublet, J 8,3 Hz, 1.6 Hz), 7,33 (1H, doublet, J 1.6 Hz).

Ethyl ester of 4-iodobenzoic acid (compound 97).

To a suspension of 10 g (40,32 mmol) 4-iodobenzoic acid in 100 ml of absolute ethanol was added 2 ml of thionyl chloride and the mixture is boiled under reflux for 3 hours, the Solvent is kept in vacuum and the residue was dissolved in 100 ml of sulphuric ether. The ether solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then kept in vacuum, and the residue was subjected to distillation with ball reflux (100aboutWith, 0.55 mm RT.cent.), receiving a colorless oily target product.

The NMR spectrum (CDCl3): of 1.42 (3H, triplet, J 7 Hz), 4,4 (2H, Quartet, J 7 G who received the following compounds: ethyl ester of 4-iodophenoxy acid, ethyl ester of 3-(4-iodophenyl)propionic acid, ethyl ester 4-(4-iodophenyl)-butane acid and ethyl ester of 5-(4-iodophenyl)pentanol acid.

Ethyl ester 6-4(4,4-dimethylthiochroman-6-yl)ethinyl)nicotinic acid (compound 99).

The reaction vessels used in this procedure was dried in a stove under vacuum, and all operations were carried out in an oxygen-free atmosphere of argon or nitrogen. To a solution of 465,7 mg (2,3019 mmol) 4,4-dimethyl-6-ethinyl-thiochroman (compound 1) in 4 ml of anhydrous tetrahydrofuran at 0aboutWith was added dropwise 1.5 ml of 1.6 M (2.4 mmol) of n-utility in hexane. The reaction mixture was stirred at 0aboutC for 10 min and at room temperature for 10 min, re-cooled to 0aboutC and then was treated with a solution of 330 mg (2,4215 mmol) of fused zinc chloride in 4 ml of anhydrous tetrahydrofuran, using dvukhkontsevoi needle. The solution was stirred at 0aboutWith in half an hour, then at room temperature for 10 minutes the Solution 426,3 mg (2,2967 mmol) of the ethyl ester of 6-chloronicotinic acid (compound 98) in 4 ml of anhydrous tetrahydrofuran translated using dvukhkontsevoi needle in suspension 430 mg (from 0.37 mmol) tetranitroaniline in 4 ml basw is using dvukhkontsevoi needle solution alkylzinc, prepared above. This mixture was stirred at room temperature for 18 h, then was suppressed by addition of 100 ml of water. The product was three times extracted with ethyl ether portions 75 ml. of Ether reactions were combined and washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified flash chromatography on silica gel using 5% ethyl acetate in hexane, and then by liquid chromatography under high pressure (Women Partial M-9 10/50; 4% ethyl acetate in hexane). Got a white solid target connection.

The NMR spectrum (CDCl3):1,36 (6N, (C) a 1.45 (3H, t, J 7 Hz), 1,96 is 2.00 (2H, m), 3,05-to 3.09 (2H, m), of 4.45 (2H, q, J 7 Hz), 7,11 (1H, d, and 8.4 Hz), 7,29 (1H, DD, J 8,4 Hz, 2.2 Hz), to 7.59 (1H, d, J 7.8 Hz), 7,66 (1H, d, J 2.2 Hz), 8,30 (1H, DD, J 7.8 Hz, 2.3 Hz), by 8.22 (1H, d, J 2.3 Hz).

Alternative synthesis.

Ethyl ester of 6-[(4,4-dimethylthiochroman-6-yl]ethinyl)nicotinic acid (compound 99).

Compound 99 was prepared as follows. A solution of 15.4 g (76,2 mmol) 4,4-dimethyl-6-ethinyl-thiochroman (compound 1) and 14.0 g (75,5 mmol) of the ethyl ester of 6-chloronicotinic acid (compound 98) in 35 ml of fresh triethylamine was degirolami and then treated in an atmosphere of nitrogen finely powder the. mesh was kept in nitrogen atmosphere at 55about20 h and then cooled to room temperature. The triethylamine drove in vacuum and the residue was distilled with 200 ml of a mixture 1:4 ethyl acetate and hexanol. The mixture was filtered through silica gel, and the filtrate was concentrated in vacuum. The obtained residue was purified flash chromatography on silica gel using 15% ethyl acetate with hexane. By recrystallization from a mixture of ethyl acetate and hexanol received target compound as a pale yellow solid.

Ethyl ester of 6-[(4,4,7-trimethylchitosan-6-yl)ethinyl]nicotinic acid (compound 100).

A mixture of 86 mg (0.4 mmol) of 4,4,7-trimethyl-6-ethinyl-thiochroman (compound 2), 85 mg (0.46 mmol) of the ethyl ester of 6-chloro-nicotinic acid (compound 98) and 0.8 ml of triethylamine was degirolami in nitrogen atmosphere and then treated with a mixture of 10 g (0.05 mmol) of copper iodide (I) and 20 mg (0.03 mmol) chloride bis(triphenylphosphine) palladium (II). The reaction mixture was heated at 55aboutC in an atmosphere of nitrogen for 18 h, then was extracted with 1.5 ml of a mixture of 40% ethyl acetate, and the rest hexane and was purified using flash chromatography on silica gel by elution with 10% ethyl acetate and hexane. Received a yellow solid target connection.

Ethyl ester of 6-[(4,4-DIMETHYLPROPANE-6-yl)ethinyl] nicotinic acid (compound 101).

Used in this example, the reactor was dried over burner under vacuum, and all operations were carried out in the absence of oxygen in the atmosphere of argon or nitrogen. To a solution of 509,4 mg (2,74 mmol) 4,4-dimethyl-6-itinirary (compound 4) in 4 ml of anhydrous tetrahydrofuran at 0aboutWith was added dropwise 1,72 ml of 1.6 M (2,75 mmol) n-utility in hexane. Stirring was started at 0aboutWith that continued for an hour, then at room temperature for 15 min, and then the solution was again cooled to 0aboutAnd was treated with a solution of 380 mg (2,79 mmol) of fused zinc chloride in 5 ml of anhydrous tetrahydrofuran, using dvukhkontsevoi needle. The resulting solution was stirred at 0aboutC for one hour and then at room temperature for 15 minutes the Solution 628,6 mg (2,74 mmol) of the ethyl ester of 6-chloronicotinic acid (compound 98) in 4 ml of anhydrous tetrahydrofuran translated using dvukhkontsevoi needle in a suspension of 380 mg (0.33 mmol) tetranitroaniline in 5 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for Tivoli at room temperature for 20 h and then the reaction was suppressed by ice and 30 ml Technomarine hydrochloric acid. The mixture was extracted with ethyl ether three times in 75 ml) and the ether extracts were combined and sequentially washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is kept in vacuum, and the residue was further purified using flash chromatography on silica gel with 10% ethyl acetate in hexane, getting solid yellow target compound.

The NMR spectrum (CDCl3): 1,36 (6N, C) of 1.44 (3H, Tr. J 7,1 Hz), 1,83-to 1.87 (2H, m), 4,22-4.26 deaths (2H, m), of 4.44 (2H, square J 7,1 Hz), to 6.80 (1H, d, J 7,6 Hz), 7,35 (1H, d, J a 8.9 Hz), 7,58 (1H, d J and 7.6 Hz), 7,60 (1H, m), of 8.28 (1H, d J a 8.9 Hz), of 9.21 (1H, s).

Ethyl ester of 6-[(2,2,4,4-tetramethyl-thiochroman-6-yl)ethinyl]nicotinic acid (compound 102).

A solution of 232 mg (1.01 mmol) of 2,2,4,4-tetramethyl-6-utilitiarian (compound 3) and 190 mg (1,03 mmol) of the ethyl ester of 6-chloronicotinic acid (compound 98) in 2 ml of triethylamine were placed in a thick-walled glass tube was degirolami, created an argon pillow and then processed poroshkovanii a mixture of 53 mg (0.28 mmol) of copper iodide (I) and 84 mg (0.12 mmol) chloride bis (triphenylphosphine)palladium (II). The mixture was again degirolami, was placed in an atmosphere of argon, and the tube is corked. The reaction mixture is kept at 55aboutIn the cue layer was separated. The aqueous layers was extracted with ethyl ether. The organic layers were combined and washed with saturated sodium chloride solution and then dried. The solvent is kept in vacuum and the resulting residue was purified using flash chromatography on silica gel by elution with 10% ethyl acetate in hexano. The result has been the target compound as a dark yellow oil.

The NMR spectrum (CDCl3): 1,32-1,43 (15 NM, m) of 1.92 (2H, s), to 4.38 (2H, q, J 7,1 Hz), 7,28 (1H, DD. J 8,3 Hz, 1.8 Hz), 7,32-7,38 (2H, m), 7,53 (1H, d, J 8,3 Hz), 8,24 (1H, d-d, J 8,2 Hz, 2.2 Hz), 9,16 (1H, d, J 2.2 Hz).

Mass spectrum m/e 379/1594 (calculated for C23H25NO2S 379,1606).

Ethyl ester of 6-[(2,2,4,4-tetramethylchroman-6-yl)ethinyl]nicotinic acid (compound 103).

A solution of 233 mg (1,09 mmol) of 2,2,4,4-tetramethyl-6-itineray (compound 5) and 209 mg (1,09 mmol) of the ethyl ester of 6-chloronicotinic acid (compound 98) in 1 ml of triethylamine was degirolami and then treated in an argon atmosphere poroshkovanii a mixture of 50 mg (0.26 mmol) of copper iodide (l) and 100 mg (0.14 mmol) chloride bis (triphenylphosphine) palladium (II). The reaction mixture was stirred in argon atmosphere at 55aboutWith over 80 hours and then cooled to room temperature. Was removed in vacuum triethylamine, and the remainder oglevee compound as a yellow oil.

The NMR spectrum (CDCl3): 1,36 (N, C) of 1.42 (3H, t, J 7.2 Hz), of 1.85 (2H, s), 4,37 (2H, J 7.2 Hz), 6,79 (1H, d, J 4 Hz), 7,34 (1H, DD J a 8.4 Hz and 2.1 Hz), 7,56 (1H, d, J 8.7 Hz), 7,60 (1H, d, 2.1 Hz), of 8.27 (1H, DD, J 8.7 Hz, 2.4 Hz), 9,19 (1H, d, J 2.4 Hz).

Mass spectrum m/e 363, 1837 (raschet. for C23H25ABOUT3N, 363,1834).

Ethyl ester of 6-[(2,2,4,4,7-pentamethyl-6-chromanol)ethinyl] nicotinic acid (compound 104).

A solution of 300 mg (1,316 mmol) 2,2,4,4,7-pentamethyl-6-itinirary (compound 9) and to 245.6 mg (1,3276 mmol) of the ethyl ester of 6-chloronicotinic acid (compound 98) in 2 ml of triethylamine was placed in a thick-walled tube and through the solution for 15 min propulsively nitrogen. The tube was then filled with argon and the solution was added finely powdered mixture of 100 mg (0,1425 mmol) chloride bis (triphenylphosphine)palladium (II) and 50 mg (0,2625 mmol) of copper iodide (I). The tube was sealed and the reaction mixture was heated to 60aboutC for 72 h the Mixture was cooled to room temperature, and kept in vacuum triethylamine. The residue was purified using flash chromatography on silica gel by elution with 10% ethyl acetate in hexane. Received a yellow solid target connection.

The NMR spectrum (CDCl3): 1,37 (6N, C) 1,38 (6N, C) of 1.44 (3H, Tr. J 7.2 Hz), of 1.85 (2H, s), 2.49 USD (3H, s), 4,43 (2H, square J 7.2 Hz), 6,70 (1 is H27ABOUT3N 377,1991).

Ethyl ester of 4-[(2,2,4,4,7-pentamethylchroman-6-yl)ethinyl] benzoic acid (compound 105).

Through a solution of 200 mg (0,877 mmol) 2,2,4,4,7-pentamethyl-6-itinirary (compound 9) and 245,3 mg (0,888 mmol) ethyl ester 4-iodobenzoic acid (compound 97) in 2 ml of triethylamine propulsively for 15 min nitrogen. Then the mixture was placed in an argon atmosphere and was treated with finely ground mixture of 50 mg (0,2625 mmol) of copper iodide (I) and 100 mg (0,1425 mmol) chloride bis(triphenylphosphine) palladium (II). Then the reaction vessel was connected with a reflux condenser and the mixture was stirred for 72 h at 55aboutC in argon atmosphere. Then drove away in the vacuum triethylamine and the residue was purified flash chromatography on silica gel using ethyl acetate in hexane. The result has been the target compound as a yellow oil.

The NMR spectrum (CDCl3):1,32 (N, singlet), to 1.37 (3H, triplet, J 7.0 Hz), of 1.80 (2H, singlet), is 2.40 (3H, singlet), 4,36 (2H, Quartet, J 7.0 Hz), 6,66 (1H, singlet), 7,42 (1H, singlet), 7,54 (2H, doublet, J 8.6 Hz), to 7.99 (2H, doublet, J 8.6 Hz).

Mass spectrum m/e 376,2038 (calculated for C25H28ABOUT3376,2038).

Ethyl ester of 4-[(2,2,4,4-tetramethylchroman-6-yl-ethinyl]benzoic acid (compound 106).

aboutC for 48 hours then drove in the vacuum triethylamine and the residue was purified using flash chromatography on silica gel with 5% ethyl acetate in hexano. Received target compound as a yellow oil.

The NMR spectrum (CDCl3): 1,33 (6N, singlet), 1,34 (6N, singlet), 1,34 (6N, C) to 1.37 (3H, Tr. I 7.2 Hz) and 1.83 (2H, s), 4,35 (2H, q, J 7.2 Hz), to 6.75 (1H, d, J 8,4 Hz), 7,24 (1H, d-d, J a 8.4 Hz and 2.1 Hz), 7,46 (1H, d, J 2.1 Hz), 7,54 (2H, d, 8.1 Hz), to 7.99 (2H, d, J 8.1 Hz).

Mass spectrum m/e 362,1880 (calculated for C24H26ABOUT3362,1881).

Ethyl ester of 4-[(4,2,2,4,4-tetramethyl-thiochroman-6-yl)ethinyl]benzoic acid (compound 107).

In a thick-walled glass tube was placed a solution to 110.7 mg (0,481 mmol) of 2,2,4,4-tetramethyl-6-utilitiarian (compound 3) and 142.3 mg (0,516 mmol) ethyl ester 4-iodobenzoic acid. The mixture was treated with finely ground mixture of 42 mg (0,221 mmol) of copper iodide (I) and 63 mg (0.09 mmol) chloride bis(triphenylphosphine) palladium. The reaction mixture was degirolami in the atmosphere of argon, and the tube is corked. The mixture was stirred at room on silica gel with 3% ethyl acetate in hexano. Got a pale yellow solid target connection.

The NMR spectrum (CDCl3): 1,37-1,42 (15 NM, multiplet), a 1.96 (2H, singlet), to 4.38 (2H, Quartet, J 7.0 Hz), 7,25 (1H, doublet-doublet, J 8.2 Hz, 1,87 Hz), 7,33 (1H, doublet, J 1.8 Hz), 7,37 (1H, doublet, J 8.2 Hz), the 7.65 (2H, doublet, 8.6 Hz), 8,01 (2H, doublet, J 8.6 Hz).

Mass spectrum m/e 378,1638 (calculated for C24H26ABOUT2, 378,1653).

Ethyl ester of 4-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethinyl[benzoic acid (compound 108).

In a thick-walled tube through a solution of 145 mg (0,7838 mmol) 4,4-dimethyl-6-ethinyl-1,2,3,4-tetrahydroquinoline (compound 6) and 220 mg (0,797 mmol) ethyl ester 4-iodobenzoic acid (compound 97) in 2 ml of tetrahydrofuran propulsively gaseous nitrogen. Then the solution was treated with finely ground mixture of 31 mg (0,163 mmol) of copper iodide (I) and 62 mg (0,088 mmol) chloride bis(triphenylphosphine) palladium (II). The tube was then filled with argon and corked. The reaction mixture is kept at 55aboutC for 72 h the Mixture was allowed to cool and then were treated with 1 ml of triethylamine. The mixture was additionally treated with powdered mixture of 15 mg (0,079 mmol) of copper iodide (I) and 30 mg (0,003 mmol) chloride bis (triphenylphosphine) palladium (II). The tube was filled with argon, corked and sociologicheski layer was separated. The aqueous layer was extracted with ethyl ether and the combined extracts are then washed with water and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is kept in vacuum and the residue was purified using flash chromatography on silica gel with 10% ethyl acetate in hexane. Received target compound as a yellow oil.

The NMR spectrum (CDCl3): 1,31 (6N, C) of 1.40 (3H, Tr. J 7.2 Hz), 1,68-1.78 g (2N, m), 3,32 is 3.40 (2H, m), 4,17 (1H, Shir. C.), to 4.38 (2H, square J 7.2 Hz), 6,41 (1H, J 8.2 Hz), to 7.15 (1H, d-d, J 8.2 Hz), 1.9 Hz), 7,39 (1H, d, J 1.9 Hz), 7,54 (2H, d, J 8,4 Hz), 8,00 (2H, d, J 8,4 Hz).

Mass spectrum m/e 333,1729 (calculated for C22H23ABOUT2N 333,1728).

The METHOD of OBTAINING ACETYLENE DERIVATIVES CHROMANE OR THIOCHROMAN General formula I

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where R1, R2, R4and R5- C1- C6- alkyl;

R3is hydrogen or C1- C6-alkyl;

X is oxygen or sulfur;

And is phenyl or pyridyl;

n is an integer equal to 0;

IN - R6group, where R6- C1- C6-alkyl,

characterized in that the compound of General formula II

< / BR>
where R1- R5have the specified values;

Z is hydrogen, metal ion or metal ion associated with the anion, being the action with the compound of the formula III

X' - A - (CH2)n- B

where X1- halogen;

A, b and n have the specified values,

in the presence of one or two catalysts, with the proviso that when Z is hydrogen, the catalyst is used iodide copper (I) and Pd(PQ3)2Cl2where phenyl - Q, and if the Z - ZnCl+as the catalyst used Pd(PQ3)4where Q is phenyl.

2. Derivatives chromane or thiochroman General formula II

< / BR>
where R1, R2, R4and R5- C1- C6-alkyl;

R3is hydrogen or C1- C6-alkyl;

X is oxygen or sulfur;

Z is hydrogen,

as an intermediate product to obtain acetylene derivatives chromane or thiochroman formula I having therapeutic activity.

 

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The invention relates to pharmaceutical industry and relates to a method of obtaining a crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide

The invention relates to veterinary medicine, in particular to methods for prevention of acute respiratory diseases in calves and can be used for prophylaxis of respiratory diseases, mainly acute respiratory infections of bacterial etiology
The invention relates to medicine, particularly cardiology, and is intended for treatment of cardiac arrhythmias

The invention relates to methods for producing compounds of formula I HOOCwhere Y is-CO-, or-CH2-;

Y is a bond or-O-;

p = 1-16; and

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and Q is phenyl, substituted C1-C3the alkoxy group

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where I R1= -OH

R2= --CH3R3= - OH

II R1= -H; R2= -C1; R3= -OH

III R1= -O--CH3; R2= -H;

R3= -Nhaving antiallergic activity, which can be used in medicine

The invention relates to medicine and can be used in pediatric patients for the treatment of complex grits I degree

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: medicine.

SUBSTANCE: before applying substitute hormonal therapy (SHT) on should evaluate antithrombogenic activity of vascular wall in women. For this purpose one should determine quantitative values of ADP-induced aggregation of thrombocytes, activity of antithrombin III in blood and fibrinolytic blood activity both before and after "cuff"-test. Then one should detect the indices calculated as the ratio of mentioned values both before and after carrying out the mentioned test. If mentioned indices are decreased against the norm by 20-40% women should be prescribed to undergo SHT at additional introduction of aspirin and supradin. The method provides prophylaxis of cardio-vascular diseases in this category of female patients due to correcting affected functional activity of vascular endothelium.

EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

FIELD: medicine, natural compounds.

SUBSTANCE: larch wood is saturated with water and extraction with ethyl acetate is carried out. Prepared extract is treated with hot water and this process is combined with distilling off a solvent. Then water-insoluble resin impurities are separated and crude product is isolated by crystallization and recrystallized. Invention provides simplifying the process.

EFFECT: improved preparing method.

2 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compounds of coumarone class, namely, to 6-nitro-2-iminocoumarin 3-carboxylic acid 4-toluidide silver salt of the formula (1): that elicits an antibacterial effect and can be used in medicine. Invention provides preparing a new compound eliciting an antibacterial effect with respect to S. aureus, E. coli, and C. albicans with mononuclear cells values 0.25; 0.5 and 7.8 mcg/ml, respectively, and with acute toxicity value LD50 for these compounds 2 460 ± 230 mg/kg.

EFFECT: valuable properties of compound.

1 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with phospholipid complexes of proanthocyanidine A2 and pharmaceutical compositions upon their basis as antiatherosclerotic agents, those for preventing and treating myocardial and cerebral infarction. Phospholipids of the above-mentioned complex should be preferably chosen out of lecithins, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine. The innovation provides the preparation to treat the above-mentioned diseases due to decreasing the quantity and burden of atheromatous plaque, decreased obstruction of carotid arteries and decreased thickness of vascular walls.

EFFECT: higher efficiency of prophylaxis and therapy.

9 cl, 11 dwg, 6 ex, 2 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

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

4 cl, 2 tbl, 568 ex

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