Water-soluble azole compounds and method for their preparing

FIELD: organic chemistry, chemical technology, medicine.

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

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

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

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

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This invention relates to a water-soluble azole compounds applicable for the treatment of severe systemic fungal infections and suitable for oral, and, in particular, for parenteral administration. More specifically, the invention relates to new water-soluble prodrugs of General formula:

where And denotes digidroksile fragment triazole antifungal compounds containing a secondary or tertiary alcohol group, R and R1each independently represents hydrogen or (C1-C6)alkyl, or their pharmaceutically acceptable salts.

Description of the prior art

Triazole antifungal compounds well. Of several known classes of one particularly effective class contains hydroxyl at the tertiary carbon atom. For example, in U.S. Patent 5648372 described that (2R,3R-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl) -1-(1H - 1,2,4-triazole-1-yl) -butane-2-ol exhibits antifungal activity.

The use of this class of compounds is limited by their low solubility in water. For example, the solubility of the above triazole compounds in water at pH 6.8 is 0,0006 mg/ml. It largely prevents the creation of appropriate parenteral dosage forms.

Odie is a solution to this problem is described in European application 829478, where the solubility of the azole antifungal agent in the water was increased by the accession to the azole fragment of a related amino acids:

Alternatively, in the International application WO 97/28169 described that phosphate fragment can be directly attached to the hydroxyl fragment at the tertiary carbon atom of an antifungal compound, an example is a compound of the formula:

In U.S. Patent 5707977 and in the International application WO 95/19983 described water-soluble prodrugs of General formula:

where X denotes the OP(O)(OH)2or easily hydrolisis ester OC(O)RN1R2.

In the International application WO 95/17407 described water-soluble azole prodrugs of General formula:

where X denotes P(O)(OH)2C(O)-(CHR1)n-OP(O)(OH)2or C(O)-(CHR1)n-(OCHR1CHR1)mOR2.

In the International application WO 96/38443 described water-soluble azole prodrugs of General formula

In U.S. Patent 5883097 described water-soluble aminocyclohexanone prodrugs, such as esters of glycerol:

Introduction postexertional fragment in Hydra is celsogarcia medicinal substance has been described as a method of obtaining a water-soluble prodrugs of hydroxyl-containing medicinal substances.

In European patent application 604910 described phosphonomethylglycine derivatives of the General formula:

where at least one of R1), R2)R3), R6)or R7)denotes co2OP(O)(OH)2.

In European patent application 639577 described derivatives phosphonomethylglycine formula T-[co2(Och2)mThe OP(O)(OH)2]nwhere T denotes taxonomy fragment, where the atom C13 has substituted 3-amino-2-hydroxypropanoate; n denotes 1, 2 or 3; m represents 0 or an integer from 1 to 6, and their pharmaceutically acceptable salts.

In the International application WO 99/38873 describes a simple O-phosphonomethyl esters diaryl-1,3,4-oxadiazoles prodrugs, discoverers of potassium channels.

Golik, J. et al, Bioorganic and Medicinal Chemistry Letters, 1996 6:1837-1842, describes the new water-soluble prodrugs of paclitaxel, such as

The INVENTION

Currently, it is found that the triazole antifungal compounds containing secondary or tertiary hydroxyl group, including (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-butane-2-ol, can be converted into prodrugs with properties superior to the properties of the previously described compounds, by attaching hospitalarias the th slice through a linking group. Specifically, the invention encompasses compounds of the formula:

where And denotes digidroksile fragment triazole antifungal compounds containing a secondary or tertiary alcohol group, R and R1each independently represents hydrogen or (C1-C6)alkyl, or their pharmaceutically acceptable salts.

Compounds of General formula I act as "prodrugs" when introduced in vivo into a biologically active source azole in the presence of alkaline phosphatase.

In a preferred embodiment of the invention And is digidroksile fragment triazole antifungal compounds containing tertiary alcohol group:

where R3represents phenyl substituted by one or more (preferably 1-3) halogen atoms;

R4represents N or CH3;

R5represents H or, together with R4can refer =CH2;

R6represents 5 - or 6-membered nitrogen cycle, which may have as substituents one or more groups selected from halogen, =O, phenyl, substituted by one or more groups selected from CN, (C6H4)-OCH2CF2CHF2and CH=CH-(C6H4)-Och2CF2CHF 2or phenyl substituted by one or more groups selected from halogen and methylpyrazole.

Nitrogen-containing heterocycles, which may denote R6include thiazolyl, pyrimidinyl or thiazolyl.

Specific examples of a include, without limitation, the following:

In addition to the use of the present invention to structures containing a tertiary alcohol group, it can be applied to antifungal agents containing a secondary alcohol group, such as:

DETAILED description of the INVENTION

As used in this description, the term "(1-C6)alkyl" refers to saturated aliphatic groups, linear or branched chain containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, etc.

The expression "pharmaceutically acceptable salt", as used herein, encompasses a phosphate salt such counterions as ammonium, metal salts, salts with amino acids, salts of amines and salts of other bases, such as piperidine or morpholine. It is envisaged that both mono-and bis-salt covered by the term "pharmaceutically acceptable salt". Specific variants of the invention include ammonium salts, is the atrium, calcium, magnesium, cesium, lithium, potassium, barium, zinc, aluminum, lysine, arginine, histidine, methylamine, ethylamine, tert.-of butylamine, cyclohexylamine, N-methylglucamine, Ethylenediamine, glycine, procaine, benzathine, diethanolamine, triethanolamine, piperidine and research. For the most preferred variant of the invention, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[(dihydroxytestosterone)methoxy]-butane, the most preferred salts are salts of tert.-of butylamine and lysine, as they can be received in the form of individual polymorphic crystalline solids of high purity with good solubility and stability.

The term "halogen"used in this description, includes chlorine, bromine, fluorine and iodine, preferably chlorine and fluorine, and most preferably fluorine.

Compounds according to this invention can be solvated or resolutionary. The preferred MES is a hydrate.

The most preferable variant of the present invention is (2R,3R-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[(dihydroxytestosterone)methoxy]-butane or its pharmaceutically acceptable salt. This prodrug has a much higher solubility (>10 mg/ml at pH 7, 5-6 mg/ml at pH of 4.3) compared to the reference compound, tapazole to use it for parenteral administration, as well as for oral administration. This compound is also stable in solution, can be isolated in crystalline form and is easily converted into the original medicinal substance in vivo.

Compounds according to this invention can easily be obtained by following the General scheme. In this method And is digidroksile fragment triazole antifungal compounds containing tertiary or secondary alcohol group, Prdenotes the corresponding protective group for hydroxyl, such as tert.-butyl, benzyl or allyl, a R and R1each independently represent hydrogen or (C1-C6)alkyl. Most preferably, when R and R1both represent hydrogen.

To implement this method we are interested source antifungal compound II turn in phosphate intermediate IV O-alkylation with chlorinated intermediate III in the presence of an appropriate base such as sodium hydride, potassium hydride, tert.-butyl sodium tert.-butyl potassium, sodium bis(trimethylsilyl)amide, such as sodium hydride plus sodium bis(trimethylsilyl)amide. This step of the reaction can be carried out in an inert organic solvent, such as tetrahydrofuran, methyltetrahydrofuran, methyl-tert.-butyl ether, diethyl ether or dimethylacetal is d, at a temperature of about 0-50°C, more preferably about 20-40°S, and most preferably about 40°C. the Most preferred base is sodium hydride, and the most preferred solvent is tetrahydrofuran. The most preferred R and R1is hydrogen.

Ester intermediate IV is then subjected to the appropriate deprotection to remove the hydroxyl-protective group Pr. The reagents used in this stage will depend on the specific hydroxyl-protective group, but is well known to specialists in this field of technology. The most preferred hydroxyl-protecting group is tert.-bucilina group which can be removed triperoxonane acid, hydrochloric acid or formic acid in a suitable inert organic solvent. Inert organic solvent can be, for example, methylene chloride, dichloroethane, methylbenzol or cryptomaterial. In the case of the preferred getprotectiondomain di-tert.-butyl (complex) ether is preferably done in triperoxonane acid in methylene chloride at a temperature of about 0-40°S, most preferably about 0-5°C.

The final product I can then be regenerated and cleaned using appropriate methods, such as treatment the NGO-phase C-18 column chromatography or solvent extraction.

The final product I can, of course, to turn the appropriate methods specified in pharmaceutically acceptable salt.

It was later found that the use of purified reagent III gives a fairly low outputs of intermediate IV (about 10-35%) in the above reaction, resulting in low outputs product I. However, if at the stage of the O-alkylation of the above reactions add a source of iodide, output, intermediate IV unexpectedly increases approximately up to 90%, thereby significantly increasing the yield of the final product I. Suppose that the addition of iodide ion can lead to the in situ formation of the corresponding iodide intermediate III' formula:

and that the use of this reagent leads to a significant increase in the yield of phosphate intermediate IV. Attempt to replace directly the intermediate III on pre-obtained intermediate III' at the first stage of the above reaction, however, was unsuccessful due to a lower stability of iodine reagent III' in comparison with the chloride intermediate III. An alternative method, which was successful, includes the use of iodine at the stage O-alkylation along with chloride intermediate III in the presence of a base, such as NaH (which also may behave in relation to iodine as a reducing agent). On Agout, what iodine is restored to ion iodine (iodide), which then converts the chloride intermediate II in situ in iodide-intermediate III', making this stage of the process. The example below illustrates the stage of O-alkylation using elemental iodine, and this is the preferred method of carrying out this reaction in order to obtain the intermediate IV.

Through education in situ iodide reagent III' by adding a source of iodide ion or by the reaction of iodine and reagent III in the presence of a strong base, sharply rising out of the ether phosphoric acid IV allows you to get the final product I with a significantly higher output.

The ion source of iodine, preferably, iodide is sodium, but they also can be lithium iodide, cesium iodide, cadmium iodide, cobalt iodide, copper iodide, rubidium iodide, barium iodide, zinc iodide and calcium iodide. On the equivalent source connection AND IT usually take about 2-3 equivalent of salt-iodide.

When elemental iodine is used at the stage of condensation, the equivalent of the starting compound AND IT take about 0.1-1.0 equivalent iodine, preferably 0.5 equivalent.

The base and the solvent used to use iodine or iodide ion (ion of iodine), the same as described above, when the reagent III is used as such.

It should be understood that if the group's Vice is her used in the above reactions, contains certain sensitive functional groups such as amino - or carboxy-group, that may cause undesirable side reactions, such groups can be protected with suitable protective groups known to specialists in this field of technology. Appropriate protective groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis. Theodora W. Greene (John Wiley and Sons, 1991). Assume that such a "protected" intermediates and final products included in the scope of this opening and claims.

It will be appreciated that some of the products covered by Formula I, may have substituents, which may lead to the formation of optical isomers. Have in mind that this invention includes within its scope all such optical isomers, as well as their epimeria mixture, i.e. the R - or S - or racemates.

Pharmaceutically active compounds in this invention can be used alone or be prepared as pharmaceutical compositions containing in addition to the active triazole ingredient pharmaceutically acceptable carrier, adjuvant or diluent. The compounds can be administered in a number of ways, such as oral, topical or parenteral (intravenous or intramuscular injection). Pharmaceutical compositions mouthbut in solid form, for example in the form of capsules, tablets, powders, etc. or in liquid form, for example in the form of solutions, suspensions or emulsions. Compositions for injection can be prepared in the form of standard doses in capsules or in containers, reusable, and they can contain additives, such as suspendresume agents and dispersing agents. The composition can be in the form of ready to use, or in the form of a powder, which is prepared for use at the time of delivery using the appropriate carrier, such as sterile water.

Or the same compound in this invention can be introduced in the form of a suppository or vaginal suppository, or they can be applied topically in the form of a lotion, solution or cream. In addition, you can enter them (at concentrations up to 10%) in an ointment consisting of a base - beeswax or soft colorless wax, combined with the need stabilizers and/or preservatives.

Compounds according to the invention are useful because of their pharmacological activity in animals, including, in particular, mammals, and most importantly, human. Specifically, the compounds of this invention are useful for the treatment or prevention of local fungal infections, including infections caused by species of Candida, Trichophyton, Microsporum or Epidermophyton. In addition, they are useful for the treatment of infections of the mucous membranes caused by Candida albicans. can also be used in the treatment of systemic fungal infections, caused, for example, Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.

Therefore, according to another aspect of the invention features (created) a method of treating a fungal infection, which consists of introducing a therapeutically effective amount of connections to the host, especially the owner of the mammal, and most importantly, the patient. The use of compounds according to this invention as pharmaceutical drugs and the use of compounds according to the invention in the manufacture of medicaments for the treatment of fungal infections is also covered.

Injected dose depends very much on the specific compounds prepared specific compositions, method of administration, the nature and status of the owner and the workpiece space and body. The choice of a particular preferred dosage and method of application remains within the competence of the physician or veterinarian. However, the connection can be entered, mainly parenterally or orally to the owner of the mammal in a quantity of about 5 mg/day to 1 g/day. These doses are average, and there may be individual cases in which there are more or less high doses, these doses are included in the scope of this invention. In addition, the introduction of compounds according to this invention can be implemented is better as a single or split (multiple) doses.

In vitro evaluation of the antifungal activity of the compounds according to the invention can be performed by determining the minimum inhibitory concentration (MIC, MBC). MIC is the concentration of the test compound that suppresses the growth of the tested microorganisms. In practice series (row) agar plates, each containing the test compound, is introduced in a certain concentration, is seeded with a strain of the fungus and then each plate is incubated for 48 hours at 37°C. the Plate is examined for the presence or absence of fungal growth and celebrate the relevant concentration. Microorganisms that can be used in the test include Candida albicans, Aspergillus fumigatus, Trichophyton spp.,, Microsporum spp., Epidermophyton floccosum, Coccidioides immitis and Torulopsos galbrata. It should be recognized that as prodrugs of some compounds according to the invention can be inactive in vitro test.

In vivo evaluation of antifungal activity of the compounds according to this invention can be accomplished in a series of dose levels by using intraperitoneal or intravenous injection or by oral administration to mice, which impose a strain of fungus (e.g., Candida albicans). The activity determined by comparing the survival rate of the treated group of mice at various dose levels after the death of the group untreated (untreated) mice. The dose at which the test compound PR is the prevention of death due to infection by 50% note.

Compounds according to this invention significantly improves the stability of the original triazole antifungal compounds, as well as produce original connection (i.e. act as prodrugs), as demonstrated in experiments S9 in human liver.

ILLUSTRATIVE EXAMPLES

Illustrated in the following examples illustrate the invention but do not claim to its limit. Abbreviations used in the examples are common abbreviations that are well known to specialists in this field of technology. Some of the used abbreviations are given below:

h = hour(s)

rt = room temperature

mmol = mmol-b(and)

g = gram(s)

THF = tetrahydrofuran

ml = milliliter(s)

l = liter(s)

Et2O = diethyl ether

EtOAc = ethyl acetate

TPA = triperoxonane acid

CH2Cl2= methylene chloride

CH3CN = acetonitrile

In the following examples, all temperatures are given in degrees Celsius. The melting temperature is determined on electrochempribor and not adjusted. Proton nuclear magnetic resonance spectrum (1H NMR) are removed on the NMR spectrometer Bruker 500, Bruker AM-300 or Varian Gemini 300. All spectra are shooting in CDCl3or D2O, unless otherwise specified. Chemical shifts are given in units (ppm) relative to tetramethylsilane (TMS) or maximum of the reference solvent, and the constants SP is n-spin interaction are given in Hertz (Hz). Multipletness signal is denoted as follows: s, singlet; d, doublet; t, triplet; q, Quartet; m, multiplet; ush., broadened signal; DD, doublet of doublets; dt, doublet of triplets; and each. D., apparent doublet, etc. Mass spectra were obtained on a mass spectrometer Kratos MS-50 or a Finnegan 4500 methods of chemical ionization (DCI, HEE, isobutene), fast atom bombardment (FAB, the Belarusian library Association) or ionisation elektrorazpredelenie (ESI).

Analytical thin-layer chromatography (TLC) carried out on plates with a fixed layer of silica gel 60F-254) and are using UV light, iodine vapor, and/or staining of methanol phosphomolybdenum acid. Reversed-phase chromatography is carried out in a glass column With 18 silica gel (Waters Corporation Preparative 18 125) under pressure slightly above atmospheric.

EXAMPLE 1

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[(dihydroxytestosterone)methoxy]-butane, sodium salt

A. (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[(di-trebuil-exitonfailure)methoxy]-butane,

To a solution of (2R, 3R-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, II (a total of 8.74 g, 20 mmol) in THF (40 ml) in an atmosphere of nitrogen was added sodium hydride (0,80 g, 60% in oil, 20 mmol) at room temperature the Resulting mixture was stirred at room temperature for 0.25 hour, and then add detriots, III (10.3 g, 40 mmol). The reaction mixture is heated at 50°C for 16 hours. Then the reaction mixture is cooled to room temperature and concentrate under reduced pressure. The residue is dissolved in Et2O and washed with N2O and brine. The organic layer is dried over MgSO4and evaporated under reduced pressure to obtain 17.0 g the above crude product IV, in the form of a resin. A small portion of this crude compound purified by reversed-phase chromatography on C-18. Substance elute 30% of CH3CN/N2About 38% of CH3CN/N2About 45% of CH3CN/N2Oh and then 50% of CH3CN/N2O. the Fractions containing the product, evaporated in vacuum to remove CH3CN. The resulting aqueous layer was then extracted with Et2O. the Ether extracts are washed with brine, dried and evaporated in a vacuum, get purified compound IV as a white solid.1NMR (300 MHz, CDCl3) 8,35 (s, 1H); 7,98 (d, 2H, J=9); 7,76 (s, 1H); 7,71 (d, 2H, J=9); 7,63 (s, 1H); of 7.36-7,27 (m, 1H); 6,86-of 6.78 (m, 2H); of 5.53 (DD, 1H, J=28,6); of 5.53 (DD, 1H, J=9,6); to 5.17 (d, 1H, J=15); to 5.03 (d, 1H, J=15); to 4.01 (q, 1H, J=7); of 1.47 (s, N); to 1.37 (d, 3H, J=7). Mass spectrum [ESI+(M+N)+]660,2 (OBS.).

C. (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2.4-differenl)-1-(1 H-1,2,4-triazole - 1-yl)-2-[ (dihydroxytestosterone] methoxy] butane, sodium salt:

Crude (2R, 3R-3-[4-4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[(di-trebuil-exitonfailure)-methoxy]-butane, IV (17 g) was dissolved in CH2Cl2(100 ml). To this solution was added TFA (50 ml) and the reaction mixture was stirred at room temperature for 0.25 hour. Then the reaction mixture is evaporated in vacuum. To the residue add H2O (200 ml), Et2O (100 ml) and EtOAc (100 ml). pH of aqueous solution was adjusted to 7.6 by the addition of solid Na2CO3and then the organic layer is separated from the water. The aqueous layer was subjected to reversed-phase chromatography on 400 g of C-18, elute, starting with N2O up to 5% of CH3CN/N2O. the Fractions containing the product, evaporated in vacuum, freeze and lyophilizers, receiving 1.5 g of the above compound I in the form of a white solid (1.5 g, 12% over two stages).1NMR (500 MHz, D2O): 8,91 (s, 1H); 7,92 (s, 1H); 7,81 (d, 2H, J=8); 7,80 (s, 1H); to 7.77 (d, 2H, J=8); 7,21 (DD, 1H, J=15,9); 6,99 (DDD, 1H, J=9,9,2); 6,91 (DDD, 1H, J=9,9,2); to 5.35 (DD, 1H, J=6,6); from 5.29 (d, 1H. J=15); a total of 5.21 (DD, 1H, J=6,6); 5,19 (d, 1H, J=15); 3,86 (kV, 1H, J=7); and 1.35 to 1.37 (d, MN, J=7). Mass spectrum [ESI- (M-N)-546,1]; the Analysis. Calculated for C23H18N5About5S1P1/Na2/3,5H2About: 42,21; N. Of 3.85; N 10,70; Na 7,03%. Found: 42,32; N 3,83; N Or 10.60; Na 7.04 Per Cent.

Di-trebucheeeeeet. III:

Di-trebucheeeeeet, III, you can get any of the following methods.

Method 1

Di-trebucit.ttf silver (6,34 g, 20 mmol), which is produced by mixing di-trebucit.ttf (polucen the rd of di-trebuetsya method (Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163) with one equivalent of silver carbonate in 50% aqueous acetonitrile and lyophilizer dry, bring in benzene together with chloromethane (35 g, 200 mmol) and stirred at room temperature for 18 hours.

The reaction mixture is filtered and the filtrate evaporated in vacuum. The remainder chromatographic on silica gel and elute the mixture of hexanol - ethyl acetate 2:1. The desired fractions evaporated to dryness, receive the above-mentioned compound III (3.7 g, 71% yield);1NMR (CDCl3): 3,63 (d, 2H, J=17); 1,51 (s, N); Mass spectrum (MH+ = 259).

Method 2

Tetrabutylammonium di-trebucit.ttf, prepared by dissolving di-trebucit.ttf [20 g, 94 mmol (obtained from di-trebuetsya method Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163)] in methanol tetrabutylammonium the hydroxide (47 ml of 1M solution, 47 mmol). Temperature ractional mixture of 23°and pH 4,33. the pH of the reaction mixture adjusted to a pH of 6.5 to 7.0 by adding methanolic tetrabutylammonium hydroxide (48 ml of a 1M solution, 48 mmol) in 0.2 hour. The reaction mixture is stirred for 0.5 hour, approximately, 26°and then evaporated in vacuum at a bath temperature of about 40°C. the Crude residue is cleaned three times by azeotropic distillation by adding toluene (3×100 ml)and the mixture is then evaporated in vacuum. The crude residue RUB clean in cold mixture of hexanol (0°C) for 1 hour and then the solid is collected by filtration, washed min is determined as being the amount of cold mixture of hexanol and dried, receiving the first portion of tetrabutylammonium di-trebotivishta in the form of a white solid (24,0 g). The mother liquor is evaporated in vacuum and then RUB clean in cold mixture of hexanol (20 ml) for 1 hour. The solid is collected by filtration, washed with a minimum amount of cold mixture of hexanol and dried, receiving the second portion of tetrabutylammonium di-trebotivishta in the form of a white solid. [(8.5 g, with 32.5 g total yield (77%)]. A solution of tetrabutylammonium di-trebotivishta (218 g, 480 mmol) in benzene (200 ml) added dropwise with stirring to chloromethane (800 g, 4535 mmol) for 1.5 h at room temperature. The reaction mixture is stirred for another 1.5 h at room temperature, and then evaporated in vacuum. The remainder in the form of oil dissolved in Et2O and filtered, precipitated white precipitate discarded. The organic layer was washed with a saturated solution of NaHCO3and H2O/brine (1:1). The organic layer is then dried with magnesium sulfate, filtered and evaporated in vacuum, obtaining caritasukraine oil (320 g). This oil chromatographic on silica gel, elute with 20% EtOAc/mixture hexanol, 25% EtOAc/mixture hexanol, then 30% EtOAc/mixture hexanol. Containing the product fractions evaporated in vacuum, receiving a Golden oil. The oil is then diluted with CH2Cl2(30 ml), evaporated in vacuum, obtaining the above-mentioned connection is Addendum III (61,3 g, 49% yield);1H NMR (benzene-d6): 5,20 (d, 2H, J=15); 1,22 (s, N).

Method 3

Idhammar (974 g, 402 ml, 5,35 mol) at 25°treated With tetrabutylammonium di-trebotivishta (250 g, 0,553 mol). Phosphate added in portions over 10 minutes. Heterogeneous mixture becomes transparent pink solution after about 15 minutes. The mixture is stirred for three hours and then on a rotary evaporator to remove iocharset when the bath temperature <30°C. the Residue is transferred into a 1 l trebuemogo ether and stirred for 15 minutes while you roll a by-product of tetrabutylammonium iodide. Tetrabutylammonium iodide is removed by filtration under vacuum through a funnel with a glass filter. The filtrate is evaporated on a rotary evaporator to yield an oil containing a 5:1 mixture of III and impurities undesirable dimer:

The mixture can be cleaned by chromatography on silica gel, while III is obtained in the form of pure compounds (oil) with the release of ˜60%.

EXAMPLE 2

(2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[(dihydroxystearic)methoxy]-butane:

A. dried in a drying Cabinet round bottom flask with a capacity of 1 l, equipped with a mechanical stirrer, input for nitrogen, addition funnel with pressure compensation, the rubber membrane and the sensor temperature is, placed sodium hydride (2,89 g, 0,069 mol, 60%) and THF (50 ml). To this stirred suspension is added dropwise within 20 minutes at room temperature was added (2R,3R)-3-[4-(4 - cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, II (10 g, is 0.023 mol) in 30 ml THF. After stirring for 45 minutes, added dropwise a solution of iodine (2,99 g, 0,0115 mol) in THF (30 ml) for 10 minutes, then 15 minutes, di-trebucheeeeeet, III (to 13.29 g 0,035 mol, ˜68% purity). The reaction mixture is stirred for 4 hours, approximately, at 41°C to complete the reaction. About the end of the reaction is judged by HPLC in the reaction. The reaction mixture was poured into ice water (100 ml). The water mixture is separated and extracted with ethyl acetate (3×50 ml)and the combined organic extracts are washed with 10% thiosulfate sodium (50 ml), water (50 ml), brine (50 ml), dried with magnesium sulfate and evaporated in vacuum, obtaining a light yellow oil (22,8 g, purity (HPLC) ˜97%). The crude product is directly used at the stage of the Century

C. In a round bottom flask, equipped with magnetic stirrer, cooling bath, the pH probe and the entrance-exit point for nitrogen, placed the product of stage A (see above) (7.5 g) in CH2Cl2(23 ml) and cooled to 0°C. To this solution while stirring, slowly add triperoxonane acid (8,8 ml) and stirred for 3 hours to complete the reaction. About okonomiyaki judged by HPLC. The reaction mixture was poured into a cold solution of 2N NaOH (64 ml). The reaction mixture was extracted with trebotivishta (2×65 ml) to remove all organic impurities. The aqueous layer containing the above product in the form of sodium salt, treated with activated charcoal (10 g) and filtered through a layer of celite. Clear filtrate acidified with 1N HCl to a pH of 2.5. The free acid the above product is extracted with ethyl acetate (2×50 ml). The combined organic extracts washed with water, dried with MgSO4, filtered and the filtrate evaporated in vacuum, obtaining 3,39 g crude above-named product.

EXAMPLE 3

Bis-lysine salt of (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1.2.4-triazole-1-yl)-2-[(dihydroxytestosterone)methoxy]-butane

The above entitled in Example 2, the product is dissolved in methanol (75 ml) and to it add L-lysine (1.8 g) and heated at 60°C for 4.5 hours. The hot reaction mixture is filtered through a layer of celite. The filtrate is evaporated to about 5 ml, is mixed with methanol (100 ml) and heated to 66°With the purpose to crystallize bis-lysine salt. Salt is collected on a Buechner funnel and dried in vacuum, obtaining 3,71 g of the above compound in the form of a crystalline substance is not quite white.

EXAMPLE 4

Salt trebutien and (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,differenl)-1-(1H1,2,4-triazole-1-yl)-2[(dihydroxytestosterone) methoxy] -butane

To a solution entitled in Example 2, the product in 50 ml of ethyl acetate added under nitrogen trebutien (5,3 ml). The reaction mixture was stirred at 40°With approximately 1 hour in order to crystallize the product. Salt of bis-trebutien collected on a Buechner funnel and dried in vacuum, obtaining of 2.21 g of the above compound in the form of a crystalline substance is not quite white.

1. Water-soluble azole compound of the formula

or its pharmaceutically acceptable salt,

where R and R1each independently represents hydrogen or (C1-C6)alkyl;

But denotes a group of the formula

where R3represents a phenyl group with one or more halogen atoms as substituents;

R4represents hydrogen or CH3;

R5represents hydrogen or, together with R4can be a =CH2;

R6represents 5 - or 6-membered nitrogen cycle, which may have as substituents one or more group selected from halogen, =O, phenyl, substituted by one or more groups selected from CN, (C6H4)-OCH2CF2CHF2and CH=CH-(C6H4)-OCH2 CF2CHF2or phenyl substituted by one or more groups selected from halogen and methylpyrazole.

2. The compound according to claim 1, wherein R3denotes 2,4-differenl.

3. The compound according to claim 2, wherein R4denotes methyl, and R5denotes hydrogen.

4. The compound according to claim 3, wherein R6denotes 4-(4-cyanophenyl)-thiazol-2-yl.

5. The compound according to claim 4, characterized in that R and R1each denotes hydrogen.

6. The compound according to claim 1, where a denotes

7. The compound (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1 - (1 H-1,2,4-triazole-1-yl) -2- [ (dihydroxytestosterone) methoxy] butane, or its pharmaceutically acceptable salt.

8. Crystalline bis-lysine salt of (2R,3R)-3-[4-(cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)2-[(dihydroxytestosterone)methoxy]butane.

9. Crystalline salt trebutien and (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-[ (dihydroxytestosterone) methoxy] butane.

10. Water-soluble azole compound of the formula

or its pharmaceutically acceptable salt,

where R and R1each independently represents hydrogen or (C1-C6 )alkyl;

In denotes digidroksile fragment triazole antifungal compounds containing secondary alcohol group of the formula

11. The method of obtaining the compounds of formula

or its pharmaceutically acceptable salt,

where R and R1each independently represents hydrogen or (C1-C6)alkyl;

But denotes a group of the formula

where R3represents a phenyl group with one or more halogen atoms as substituents;

R4represents hydrogen or CH3;

R5represents hydrogen, or together with R4can be a =CH2;

R6represents 5 - or 6-membered nitrogen cycle, which may have as substituents one or more group selected from halogen, =O, phenyl, substituted by one or more groups selected from CN, (C6H4)-Och2CF2CHF2and CH=CH-(C6H4)-Och2CF2CHF2or phenyl substituted by one or more groups selected from halogen and methylpyrazole, which is

(a) the reaction is AI the compounds of formula A-HE with the compound of the formula

in which R and R1defined above, and Pr represents a protective group for hydroxyl, in an inert organic solvent in the presence of a base at a temperature of about 25-50°C, with the formation of the intermediate of formula

where the value of Pr, And R and R1given above, and

(b) removing the protective groups of Pr in the usual way with the formation of the compounds of formula

and, if required, converting the compounds I in the usual ways in its pharmaceutically acceptable salt.

12. The method according to claim 11, characterized in that the protective group Pr denotes a tertiary butyl.

13. The method according to claim 11, characterized in that the solvent used in stage (a)is tetrahydrofuran.

14. The method according to claim 11, characterized in that the base used in stage (a)is a sodium hydride.

15. The method according to claim 11, characterized in that ishodnym substance AND HE is



 

Same patents:

FIELD: coordination compounds synthesis.

SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.

EFFECT: increased assortment of complexes with useful medicine-destination properties.

14 cl, 4 dwg, 30 ex

The invention relates to fosfororganicheskim the compound containing group polimerizacionnye

The invention relates to a method for phenylene and naphthaleneboronic acids, which can be used as extractants uranium and base metals, as well as insecticides and other biologically active substances

The invention relates to new phosphorylated derivative of phenylacetic acid of the formula (II), where R1means-CH2THE OP(O)(OH)2and R2means HE; R1means-CH3and R2means-OP(O)(OH)2

The invention relates to the chemistry of organophosphorus compounds, particularly to a method of producing esters of phosphorus acids, which can find use as plasticizers, additives for lubricating oils and liquid fuels, additives for polymers, as well as extractive agents and complexing agents, herbicides, insecticides and antibioticsa funds

The invention relates to new thiosemicarbazones formula I

< / BR>
where R4represents N or CH3, R5is CHR, benzyl or ortho - or para-substituted benzyl, R represents H, CH3CH2CH3CH2CH2-CH3or CH(CH3)2, R' represents the residue of phosphoric acid, salt of phosphoric acid or-S-S-R" group, R" is CH2CH2OTHER6CH2CH2HE, CH2COOR7, ortho - or para-substituted C1-C3alkylphenyl or ortho - or para-substituted nitrophenyl, R6represents H, C1-C4acyl group, trifluoracetyl, benzoyloxy or substituted benzoyloxy group, R7represents H, C1-C4alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl

-chloroalkilphosphates" target="_blank">

The invention relates to a method for producing Tris--chloroalkilphosphates General formula (СlR)3)P= O, where R is a C2C3-alkyl, which are used as flame retardant plasticizers in the production of nitrolingual, nitrate cellulose ethers, polyurethanes, polymetylmetacrylate and flame retardants for electrical insulating varnishes

FIELD: organic chemistry, medicine, pharmacy.

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

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

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology.

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

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

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

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

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

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

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

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

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

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

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

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