Derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-d-ribofuranose and method of their obtainment

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

 

The technical field

The present invention relates to a new derivative of 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose and method thereof, which is useful as intermediate compounds in the production of gemcitabine.

Prior art

Gemcitabine formula (A), a drug for the treatment of non-small cell lung cancer (NSCLC), is a synthetic nucleoside analogue with nucleobase cytosine, stereochemical oriented up β-direction when the atom C-1 ribofuranose skeleton.

Gemcitabine can be obtained from compounds lactol, as shown in the Reaction Scheme 1 through activated ribofuranose intermediate compound having an active leaving group:

The Reaction scheme 1

where P1is protective hydroxy-group and L is a leaving group.

More specifically, gemcitabine can be obtained 1A) the introduction of a reactive leaving groups (L) to C-1 ribofuranose ring connection lactol () to obtain the activated ribofuranose intermediate compound (C), and 1b) glycosylation of the compounds of formula (C) cytosine with the formation of N-glycosidic bonds.

In the reaction scheme 1 stage glycosylation 1) passes through the mechanism of bimolecular nucleophilic substitution (S N2), and, therefore, when receiving gemcitabine is an important high purity α-anomer of the compound (C)having a leaving group (L), oriented down. Accordingly, there have been many attempts to develop a way stereoselective introduction of the leaving group (L) to C-1 of the ribofuranose ring connection lactol ().

For example, US patents No. 4526988 and 5453499 reveal activated ribofuranose intermediate compound, such as 1-α-halogenosilanes having a halogen leaving group introduced by s-1 the ribofuranose ring. More specifically, US patent No. 4526988 describes a method of deriving 1-α-halogenosilanes formula (F) 2A) the interaction of 1-hydroxy-group of compounds lactol formula (D) source of acetyl, such as acetic anhydride, to obtain 1-azetilproizvodona formula (E) and (2b) by the interaction of 1-azetilproizvodona formula (E) with gaseous HBr and HCl to obtain 1-halogenosilanes, as shown in reaction Scheme 2:

The Reaction scheme 2

where R' is a protective hydroxy-group, Ac is acetyl and X is Br or Cl.

However, this method leads to a low yield of the desired α-halogenerator because of its low stereoselectivity.

The US patent No. 5453499 discloses a method of obtaining α-enriched 1-galogenirovannyie (N), with value α:β from 9:1 to 10:1, interaction βsulfonate compounds of the formula (G) with a source of halide in an inert solvent, as shown in Reaction Scheme 3:

The Reaction scheme 3

where P ' is a protective hydroxy-group, such as benzoyl, R" is a sulfonate, and Y is halogen.

However, 1-sulfonate compounds of the formula (G), used as the starting material in this method is obtained from the connection lactol the method described in US patent No. 5401861, relate α:β about 1:4 and, thus, the total ratio of stereoselectivity (α:β) for 1-halogenerator is about 3:1.

Moreover, previous 1-α-halogenfrei with a secure 2 - and 5-hydroxy-group, for example, benzoline groups exist only in the form of oil that is more difficult to handle and store than solid form, in addition to their selection of mix αand β-isomers requires uneconomical way of column chromatography. Thus, there is a need to develop better ways of receiving gemcitabine using α-halogenfrei as an intermediate connection.

The invention

Accordingly, the main purpose of this image is to be placed is the provision of a new derivative of 1-α -halogen-D-ribofuranose in solid form, which can be purified by a simple method of purification such as recrystallization, suitable for mass production.

Another objective of the present invention is the provision of a highly stereoselective method of obtaining these compounds are of high purity and with high yield.

Also another purpose of the present invention is to provide compounds which can be used as an intermediate in the above method.

In accordance with the first aspect of the present invention provides a derivative of 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I) in solid form:

where

R1is benzoyl or

R2is hydrogen, cyano, halogen, carbalkoxy, nitro, C1-2alkoxy, C1-2the alkyl or dialkylamino; and

X is Cl, Br or I.

In accordance with another aspect of the present invention provides a method for deriving 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I), which includes stages:

(i) restore the connection 1-uxoribus formula (II) with a compound lactol formula (III);

(ii) the interaction of the compounds of formula (III) with getagentstate compound of formula (IV) in the presence of the warping obtaining 1-phosphate furanose derivative of the formula (V); and

(iii) the interaction of the compounds of formula (V) with a source of halogen, followed by recrystallization of the resulting product with derivatization 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I):

where R1, R2and X have the same values as defined above; and R3is stands, ethyl or phenyl, preferably phenyl.

In accordance with another aspect of the present invention provides a new 1-phosphate furanose derivative of the formula (V), which can be used as intermediate compounds in obtaining the derived 1-α-halogen-D-ribofuranose of formula (I):

where R1, R2and R3have the same values as defined above.

Detailed description of the invention

The term "enriched anomer"used herein means a mixture of anomers, with the content of a certain anomer more than 50%, preferably mostly pure anomer.

Of the compounds of formula (I) of the present invention preferred are those in which R2is hydrogen.

Derived ribofuranose of formula (I) according to the invention is characterized by the presence of 3-hydroxy-group-protected biphenylcarboxylic group. Also derived according to izobreteny who may have biphenylcarboxylic group as a protective 5-hydroxy-group.

Thus, the derived 1-α-halogenosilanes according to the invention can be obtained in the form of a solid substance and, accordingly, it can be easily purified by a simple method of purification such as recrystallization, to a high of 99.5% purity or higher.

Also, the derived 1-α-halogenosilanes formula (I) according to the invention may be combined with cytosine in ordinary glycosylation reactions with receiving gemcitabine, with the cytosine residue at C-1 ribofuranose rings, oriented up β-configuration).

When receiving gemcitabine through a stage of glycosylation using the derived 1-halogenosilanes very important clean α-halogenerator. If the content β-halogenerator increases, the stereoselectivity of the glycosylation reaction is markedly reduced, resulting in low yield of the desired β-nucleoside gemcitabine.

Non-obvious way of deriving 1-galactofuranose formula (I) described in the Reaction Scheme 4.

The reaction scheme 4

where R1, R2, R3and X have the same meanings as described above.

In the Reaction Scheme 4 derived 1-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I) can be obtained in a form having a high content of α-anomer of 99.5% or higher, by (i) in the formation of compounds 1-uxoribus formula (II) in accordance with the usual methods of obtaining connection lactol formula (III), mix αand β-anomers; (ii) interaction of the compounds of formula (III) with a compound of getagentstate formula (IV) in the presence of a base to obtain β-enriched 1-postattorney formula (V)with value β/α 10 or more; and (iii) interaction of the compounds of formula (V) with a source of halide to obtain the compounds of formula (I).

The use of new furanone intermediate compounds of formula (V)with phosphate leaving group, is a feature of non-obvious way to obtain 1-halogenosilanes formula (I)having a high content of α-anomer.

Thus, at stage (ii) obtain phosphate furanose formula (V) from compound lactol formula (III) β-anomer phosphate can be obtained with a high ratio β/αgreater than 10. Subsequent stage (iii) can be carried out continuously without isolating the intermediate compound with obtaining α-halogenfrei formula (I) with a high ratio α/βat least 10.

Moreover, in accordance with the present invention α-halogenfree is obtained in the form of a solid substance when biphenylcarboxylic group adopted as a protective 3 - and/or 5-hydroxy-group ribofuranose rings, and solid form can be easily purified to a high purity of 99.5% or above simple method of cleaning, which is what makes it possible for required β -nucleoside having a high ratio β/α from 4 to 14. This high ratio β/α is significantly higher than the ratio of β/α from 2 to 3, achievable by conventional means.

More specifically, at the stage (i) of Reaction Scheme 4, the compound lactol formula (III) can be obtained by reduction of compounds of formula (II) regenerating agent, as described in patent US 4526988 and 5464826. Connection 1-uxoribus formula (II)used as feedstock at the stage (i)can be obtained by a method including protection phase 3-hydroxy-group of compounds of formula (VI) biphenylcarboxylic protecting group, followed by hydrolysis of the resulting product in the presence of a base to obtain enantiomer 3R-carboxylate of the formula (VII):

where R2has the same meaning as above, R4is stands or ethyl, R5is1-5the alkyl and M is NH4, sodium or potassium.

The solvent suitable for use on stage (i)is tetrahydrofuran, diethyl ether or dioxane; and regenerating agent can be alumoweld lithium di-from-butylaminoethyl or threetert-butoxyaniline lithium, preferably threetert-butoxyaniline lithium; and the restoration can be conducted the ri at room temperature for 1 to 2 hours after addition of the reducing agent at -50 to -20° C.

At this stage (i) restore the connection lactol formula (III) is obtained in the form of mixtures αand β-anomers in a ratio of from 1:1 to 2:1; and the next stage (ii) can be performed after the selection of each anomer obtained in stage (i) or conducted without such a selection.

At stage (ii) 1-phosphate furanose formula (V) can be obtained by the coupling of compounds of formula (III) with a compound of getagentstate formula (IV) in the presence of a base to obtain β-enriched compounds of the formula (V)with value β/α 10 or more. At this stage of the phosphate leaving group can be dimethylphosphate, diethylphosphate or diphenylphosphate, preferably by diphenylphosphate.

Stage (iii) can be carried out after isolation of the desired β-anomer obtained in stage (ii) recrystallization using such solvents as water, ethanol, propanol, isopropanol,n-butanol, ethyl acetate and mixtures thereof, preferably isopropanol or a mixture of isopropanol - water. Also, this stage can be carried out with the crude product of stage (ii) without allocation process.

Connection getagentstate formula (IV) may be used in amounts ranging from 1.1 to 1.5 molar equivalents, relative to lactulosa to the compound of formula (III). The compound of formula (IV) is the commercial and available or can be easily obtained in accordance with conventional methods, open inBichem. Preps., 1, 50 (1951) orJ. Chem. Soc.,2921 (1949). Stage (ii) can be facilitated by adding a catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinedione.

Also the base used to neutralize the acid obtained in stage (ii)may be selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine, preferably triethylamine, which can be used in amounts ranging from 1.2 to 2.0 molar equivalents, relative to lactulosa to the compound of formula (III). The solvent used in stage (ii)may be benzene, toluene, acetonitrile, tetrahydrofuran, ethyl acetate, methylene chloride or chloroform, preferably, toluene, and which is carried out at -25 to 50°C for from 2 to 10 hours.

In addition, at stage (iii) interaction 1-phosphate furanose formula (V) with a source of halide followed by recrystallization of the resulting product can be obtained in high purity α-anomer of formula (I) of 99.5% or higher (i.e., content β-anomer less than 0.5%).

The source of halide, which can be used in stage (iii), includes HCl/acetic acid, HBr/acetic acid, HBr/propionic acid, trialkylsilanes, lithium halide, sodium halide, a halide of cesium, potassium halide, halogen is of tetraalkylammonium and mixtures thereof; of which preferred are 30% HBr/acetic acid, 30% HBr/propionic acid, tetrabutylammonium iodide, tetrabutylammonium bromide, trimethylsilylmethyl, trimethylsilylmethyl, trimethylsilane and the mixture trimethylsilyloxy - lithium bromide. Such a source of halide is used in an amount of 5 to 30 molar equivalents, preferably from 10 to 20 molar equivalents relative to the compound of formula (V).

In the case of 1.0 M HCl/acetic acid, 30% HBr/acetic acid, 30% HBr/propionic acid as the source of halogen is they are used in undiluted form, while other sources of halide can be used diluted such solvents as methylene chloride, dibromethane, dichloroethane, chloroform, THF, 1,4-dioxane, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide.

Stage (iii) can be carried out in a solvent such as methylene chloride, dibromethane, dichloroethane or chloroform at a temperature in the range from 0 to 50°C, preferably from 10 to 30°C for from 30 minutes to 24 hours.

The resulting 1-halogenosilanes is a mixture of αand β-anomers, with value α/β at least 10, and the desired α-anomer can be isolated from the mixture by recrystallization using a solvent such as methanol, ethanol,isopropanol, acetonitrile, water or mixtures thereof, preferably, isopropanol or a mixture of isopropanol - water to obtain 1-α-halogenosilanes with high purity of 99.5% or more.

An obvious way to obtain 1-α-halogenfrei formula (I)using 1-postattorney formula (V) as an intermediate compound, gives the total yield from 65 to 75%, which is significantly higher than that achievable by conventional means (the total yield of about 45%).

Subsequent Receipt and Examples are given only for illustration and do not limit the scope of the invention.

In the following Examples of the preparation and Examples, the term "-OCOBiPh" or "BiPhOCO-" refer to

HPLC analyses of the compounds of formula (V) were carried out on a column of YMC pack pro C18 RS (4,6×150 mm, 5 μm) using as eluent a mixture of buffer and methanol (17:83, V/V); and the compounds of formula (I) in column Capcellpak MG C18 RS (4,6×150 mm, 5 μm) using as eluent a mixture of buffer and methanol (1:4, V/V). The buffer was obtained a mixture of 13.8 g NaH2PO4and 1 l of distilled water and adding N3PO4to a pH of 2.5.

Example of getting a 1: Getting D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilose-5-benzoyl-3-(4-phenyl)benzoate

(compound of formula (II))

15 g of D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-yl) - Rev. SHL-3-(4-phenyl)benzoate (method of obtaining described in WO 2006/009353 (stage 1 of Method a of Example 3 p.14-15)) was dissolved in 150 ml of methylene chloride, and when mixing it added dropwise 6.9 ml of pyridine. In the solution slowly added to 7.4 ml of benzoyl chloride dissolved in 40 ml of methylene chloride, keeping the temperature from 5 to 10, followed by stirring for 7 hours at room temperature. The resulting mixture was neutralized 105 ml of 1N HCl and then added water. The organic layer was separated, sequentially washed with 100 ml saturated sodium bicarbonate and 100 ml of brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was recrystallize from diethyl ether/hexane (5:1, V/V)with a 16.8 g of the titled compound as white solids (yield: 86%).

1H-NMR (300 MHz, CDCl3): 4,90˜and 4.75 (DDD, 2H), 5,10 (DD, 1H), by 5.87 (DDD, 1H), 7,65˜to 7.50 (m, 5H), 7,78˜to 7.67 (m, 3H), 7,81 (d, 2H), 8,13 (d, 2H), 8,23 (d, 2H).

TPL: 130-131°C.

Example of getting 2: Obtaining D-Erythro-2-deoxy-2,2-Diptera-pentofuranose-1-ilose-3,5-di(4-phenyl)benzoate (the compound of formula (II))

20 g of D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilose-3-(4-phenyl)benzoate was dissolved in 300 ml of chloroform, with stirring, it was added dropwise to 9.5 ml of pyridine. The solution is slowly added 10.1 ml of benzoyl chloride dissolved in 55 ml of chloroform, followed by stirring for 6 hours at anatoy temperature. The resulting mixture was neutralized 140 ml of 1N HCl and successively washed with 150 ml water, 150 ml saturated sodium bicarbonate and 150 ml of brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was recrystallize from ethyl acetate/hexane (3:1 V/V)with 21.8 g of the named compound as a white solid (yield: 72%).

1H-NMR (300 MHz, CDCl3): 4,72˜4,79 (m, 2H), to 5.03 (q, 1H), of 5.84˜USD 5.76 (m, 1H), of 7.48˜7,44 (m, 6H), 7,72˜of 7.60 (m, 8H), 8,15˜8,07 (m, 4H).

TPL: 137-139°C.

Example 1: Obtain 1-α-bromo-2-deoxy-2,2-Diptera-D-ribofuranosyl-5-benzoyl-3-(4-phenyl)benzoate (the compound of formula (I); R1=benzoyl and R2=4-phenyl)

Step 1) Obtain 2-deoxy-2,2-Diptera-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate (the compound of formula (III))

13.5 g tri-tert-butoxyaniline lithium dissolved in 160 ml of THF and was stirred for 30 minutes at room temperature and then cooled to -40°C. To the solution was added the compound obtained in the example of obtaining 1, dissolved in 80 ml of THF, the mixture is slowly heated to room temperature and left to react at this temperature for 2 hours. Upon completion of the reaction, the reaction mixture was added dropwise to 220 ml of 1N HCl for RA is the provision of an excess of tri-tert-butoxylated lithium. Organic (THF) and water, the layers separated, and the aqueous layer was Proektirovanie 220 ml of diethyl ether. The ether extract was combined with THF layer was successively washed with 220 ml of water, 220 ml of saturated sodium bicarbonate and 220 ml of brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified flash chromatography, getting to 18.3 g of the named compound as a pale yellow syrup (yield: 91%).

1H-NMR (300 MHz, CDCl3): 3,89˜3,91 (d, 1H), br4.61˜to 4.81 (m, 2H), 5,31˜of 5.92 (m, 2H), 7,26˜of 7.70 (m, 10H), 8,05˜8,16 (m, 4H).

Stage 2) Obtain 2-deoxy-2,2-Diptera-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoyl-1β-diphenylphosphate (compound of formula (V))

of 18.3 g of compound obtained in stage 1, was dissolved in 146 ml of toluene and added to it of 6.7 ml of triethylamine. The solution is dropwise added to 12.4 ml diphenylchlorophosphine dissolved in 37 ml of toluene, followed by stirring for 4 hours at room temperature. Upon completion of the reaction the remaining triethylamine was neutralized by addition of 48 ml of 1N HCl, the layers of toluene and water were separated and the aqueous layer was Proektirovanie 48 ml of diethyl ether. The ether extract was combined with the toluene layer and sequentially washed with water, saturated sodium hydrogen is saturated with brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a mixture of αand β-phosphates in the form of solids. The mixture researched1H NMR and found that the ratio of αphosphate:β-phosphate was 1:10,6. β-phosphate was selectively recrystallize from isopropanol/water (3:1 V/V)with 26.5 g of the titled compound as white solids (yield: 87%).

1H-NMR (300 MHz, CDCl3): 4,56-of 4.25 (m, 3H), 5,80 (m, 1H), 5,95 (t, 1H), 7,44-6,98 (m, 16H), 7,51 (d, 2H), EUR 7.57 (d, 2H), 7,89 (d, 2H), 8,01 (d, 2H).

So pl.: 101-103°C.

HPLC purity (% peak): α-phosphate anomer of 1.76%, β-phosphate anomer 98,24%.

Stage 3) Obtaining 1-α-bromo-2-deoxy-2,2-Diptera-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate (the compound of formula (I))

of 22.8 g of compound obtained in stage 2, was added to an 80.5 ml of 30% HBr/acetic acid, followed by stirring for 6 hours at room temperature. Upon completion of the reaction, the resulting mixture was diluted with 400 ml of methylene chloride and poured onto 500 ml of ice/water. The organic layer was separated, sequentially washed with water, saturated sodium bicarbonate and brine, dried over anhydrous MgSO4and concentrated under reduced pressure to obtain a mixture of αand β-bromoaniline as Tverdov the matter. The mixture researched1H NMR and found that the ratio of α-bromo:β-bromo amounted to 10.7:1. α-bromoguanine selectively has recrystallize from isopropanol, having 17.0 g of the named compound as a white solid (yield: 82%).

1H-NMR (300 MHz, CDCl3): 8,19 (d, 2H), of 8.06 (d, 2H), 7,73 (d, 2H), 7,63 (d, 2H), of 7.64-7,41 (m, 6H), 6,56 (d, 1H), ceiling of 5.60 (DD, 1H).

So pl.: 111-112°C.

HPLC purity (% peak): α-bromoalkanes 99,74%, β-bromoalkanes 0,26%.

Example 2: Obtain 1-α-bromo-2-deoxy-2,2-Diptera-D-ribofuranosyl-3,5-di(4-phenyl)benzoate (the compound of formula (I); R1=4-biphenylcarboxylic and R2=4-phenyl).

Step 1) Obtain 2-deoxy-2,2-Diptera-D-ribofuranosyl-3,5-di(4-phenyl)benzoate (the compound of formula (III))

8,66 g tri-tert-butoxyaniline lithium dissolved in 120 ml of THF and was stirred for 30 minutes at room temperature and then cooled to -40°C. To the solution was added the compound obtained in Example Getting 2 dissolved in 100 ml of THF, and stirred for 1 hour at room temperature. Upon completion of the reaction, the reaction mixture was added dropwise 142 ml of 1N HCl to decompose excess of threetert-butoxyaniline lithium, THF and water, the layers separated, and the aqueous layer was Proektirovanie 150 ml of diethyl ether. The ether extract was combined the with the THF layer was successively washed with water, saturated sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was recrystallize from toluene, having a 13.4 g of the titled compound as white solids (yield: 89%).

1H-NMR (300 MHz, CDCl3): 3,45 (s, 1H), 3,8 (C)4,85˜4,50 (m, 3H), 5,8˜to 5.4 (m, 2H), 7,49˜the 7.43 (m, 6H), 7,71˜to 7.61 (m, 8H), 8,18˜to 8.12 (m, 4H).

So pl.: 156-158°C.

Stage 2) Obtain 2-deoxy-2,2-Diptera-D-ribofuranosyl-3,5-di(4-phenyl)benzoyl-1β-diphenylphosphate (compound of formula (V))

13 g of compound obtained in stage 1, was dissolved in a mixture of 130 ml of toluene and 100 ml of methylene chloride, and added to it to 5.1 ml of triethylamine. To the resulting mixture dropwise added with 7.6 ml of diphenylchlorophosphine and was stirred for 5 hours at room temperature. Upon completion of the reaction the solvent was removed under reduced pressure, the resulting solid was dissolved in 130 ml of methylene chloride and added 65 ml of 1N HCl. The organic layer was separated, sequentially washed with water, saturated sodium bicarbonate and brine, dried over anhydrous MgSO4and concentrated under reduced pressure to obtain a mixture of αand β-phosphates in the form of solids. The mixture researched1H NMR and found that the rate of α phosphate:β-phosphate was 1:10,8. β-phosphate was selectively recrystallize from isopropanol, receiving 15.6 g of the named compound as a white solid (yield: 83%).

1H-NMR (300 MHz, CDCl3): 4,70-and 4.40 (m, 3H), 5,90 (m, 1H), between 6.08 (t, 1H), 7,70˜was 7.08 (m, 24H), 8,15˜8,04 (DD, 4H).

So pl.: 145-147°C.

HPLC purity (% peak): α-phosphate anomer of 1.29%, β-phosphate anomer 98,71%.

Stage 3) Obtaining 1-α-bromo-2-deoxy-2,2-Diptera-D-ribofuranosyl-3,5-di-(4-phenyl)benzoate (the compound of formula (I))

13 g of compound obtained in stage 2, was dissolved in 83,2 ml of 30% HBr/acetic acid and was stirred for 7 hours at room temperature. To the solution was added 50 ml of a mixture of ice/water and filtered, the resulting solid substance. The filtered solid was a mixture of αand β-bromoaniline, and1H NMR analysis showed that the ratio was α-bromo:β-bromo 10,9:1. α-bromoguanine selectively has recrystallize from ethanol, having to 8.45 g of the titled compound as white solids (yield: 83%).

1H-NMR (300 MHz, CDCl3): 4,89˜4,22 (m, 3H), 5,62 (DD, 1H), 6,55 (d, 1H), 7,73˜7,42 (m, 14H), 8,63˜8,11 (DD, 4H).

So pl.: 151-153°C.

HPLC purity (% peak): α-bromoalkanes 99,67%, β-bromoalkanes 0,33%.

Example 3: Obtain 1-α-bromo-2-deoxy-2,2-Diptera-D-ri is furanosyl-3-benzoyl-5-(4-phenyl)benzoate (get in situ)

6.5 g tri-tert-butoxyaniline lithium dissolved in 100 ml of THF and was stirred for 30 minutes at room temperature, and cooled to -40°C. To the solution is dropwise added 10 g of the compound obtained in the Example of Obtaining 1, dissolved in 50 ml of THF, and stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction mixture was added dropwise to 120 ml of 1N HCl to decompose excess of threetert-butoxyaniline lithium, THF and water, the layers separated, and the aqueous layer was Proektirovanie 150 ml of diethyl ether. The ether extract was combined with THF layer was successively washed with water, saturated sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 10.5 g of a residue in the form of syrup.

The resulting residue was dissolved in 100 ml of toluene and added to 4.0 ml of triethylamine. To the resulting mixture dropwise added 6.4 ml of diphenylchlorophosphine dissolved in 30 ml of toluene, followed by stirring for 4 hours at room temperature. Upon completion of the reaction to neutralize the remaining triethylamine to the mixture was added 30 ml of 1N HCl, the layers of toluene and water were separated, and the aqueous layer was Proektirovanie 30 ml of diethyl apiary extract was combined with the toluene layer and sequentially washed with water, saturated sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, obtaining 14.9 g of the mixture αand β-phosphates in the form of syrup. The mixture researched1H NMR and found that the ratio of αphosphate:β-phosphate was 1:10,3.

Then to the mixture of phosphates added to 57.2 ml of 30% HBr/acetic acid and was stirred for 7 hours at room temperature. Upon completion the reaction mixture was diluted with 280 ml of methylene chloride, poured into ice/water and the separated layer of methylene chloride. The layer of methylene chloride were sequentially washed with a mixture of ice/water, saturated sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a mixture of αand β-isomers in the form of solids. The mixture researched1H NMR and found that the ratio of α-bromo:β-bromo amounted to 10.5:1. α-bromoguanine selectively has recrystallize from isopropanol, having obtained 8.0 g of the above compound as a white solid (yield: 70%).

Data1H NMR, and so pl. were the same as those found in stage 4 of Example 1.

HPLC purity (% peak): α-bromoalkanes 99,51%, β-bromoalkanes of 0.48%.

Example 4: Obtain 1-α-iodo-2-dezo the si-2,2-Diptera-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate

5.6 ml of trimethylsilylmethyl added to 40 ml of methylene chloride, were added 1.8 g of the compound obtained in stage 2 of Example 1, and the mixture was stirred for 0.5 hour at room temperature. While cooling in an ice bath the mixture was dropwise added to 100 ml of saturated sodium bicarbonate and stirred for 0.5 hours. The layer of methylene chloride was separated, dried over anhydrous MgSO4and concentrated under reduced pressure, obtaining the mixture αand β-isomers in the form of solids. The mixture researched1H NMR and found that the ratio of α-iodo:β-iodo amounted to 14.2:1. α-iodosobenzene selectively has recrystallize from isopropanol, receiving of 1.36 g of the named compound as a white solid (yield: 92%).

1H-NMR (300 MHz, CDCl3): 8,24 (d, 2H), of 8.06 (d, 2H), 7,74 (d, 2H), 7,66 (d, 2H), of 7.64-the 7.43 (m, 6H), 6,93 (d, 1H), ceiling of 5.60 (DD, 1H), 4,86˜and 4.68 (m, 3H).

HPLC purity (% peak): α-Iodoral 99,81%, β-Iodoral of 0.18%.

Comparative Example 1: Receive 1-α-iodo-2,2-debtor-2-deoxy-D-ribofuranosyl-3,5-dibenzoate

The named compound was obtained in accordance with the method disclosed in U.S. patent No. 5453499, as described below.

To 1 g of 2,2-debtor-2-deoxy-D-ribofuranosyl-3,5-Dibenzoyl-1-β-(p-Brabanthal)sulfonate was added and 80 ml of tetrahydrofuran and 80 ml of tetrabutylammonium iodide, and the mixture is boiled under reflux for 3.5 hours. The resulting mixture consisted of a mixture of α-iodo β-iodo analysis1H NMR showed that the ratio of α-iodo:β-iodo amounted to 10:1.

To highlight α-iodosobenzene the mixture was cooled and diluted with dichloromethane and water. The organic layer was separated, sequentially washed 1N HCl, sodium carbonate, brine and water, dried over anhydrous MgSO4and concentrated under reduced pressure to obtain a residue in the form of syrup. The resulting residue was purified flash chromatography on silica gel (toluene/hexane (2:1, V/V))with 302 mg of the titled compound (yield: 45%).

1H-NMR (300 MHz, CDCl3): to 8.12 (m, 4H), 7,72˜to 7.4 (m, 6H), 6,92 (d, 1H), ceiling of 5.60 (DD, 1H), 4,91 ˜to 4.62 (m, 3H).

Although the invention has been described with regard to the above-mentioned specific embodiments, it should be realised that the person skilled in the art can be made of various modifications and changes also fall within the scope of the invention as defined in the attached claims.

1. Derived 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I) in solid form

where R1is benzoyl or

R2is hydrogen; and

X is Cl, Br or .

2. The derivative according to claim 1, where the content β-anomer is 0.5% or less.

3. The method of deriving 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I), which includes stages:

(i) restore the connection 1-uxoribus formula (II) with a compound lactol formula (III);

(ii) the interaction of the compounds of formula (III) with getagentstate compound of formula (IV) in the presence of a base to obtain 1-fosfaturicescomu derivative of the formula (V); and

(iii) the interaction of the compounds of formula (V) with a source of halogen, followed by recrystallization of the resulting product with derivatization 1-α-halogen-2,2-debtor-2-deoxy-D-ribofuranose of formula (I)

where R1, R2and X have the same values as defined in claim 1; and R3is phenyl.

4. The method according to claim 3, in which the base is used in stage (ii), selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine.

5. The method according to claim 4, in which the base is used in stage (ii) is triethylamine.

6. The method according to claim 3, in colorometric halogen, used in stage (iii)is selected from the group consisting of HCl/acetic acid, HBr/acetic acid, HBr/propionic acid, trialkylsilanes, lithium halide, sodium halide, cesium halide, potassium halide, of tetraalkylammonium halide and mixtures thereof.

7. The method according to claim 6, in which the source of halogen is used in stage (iii)is selected from the group consisting of 30% HBr/acetic acid, 30% HBr/propionic acid, tetrabutylammonium iodide, tetrabutylammonium bromide, trimethylsilylmethyl, trimethylsilylpropyne, trimethylsilylpropyne and the mixture trimethylsilyloxy - lithium bromide.

8. The method according to claim 3, in which the recrystallization stage (iii) is carried out from a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, water and mixtures thereof.

9. The method according to claim 8, in which the recrystallization stage (iii) is from isopropanol or mixture isopropanol is water.

10. The method according to claim 3, in which the derivative of formula (I) is obtained with a purity of 99.5% or higher.

11. 1-Phosphate furanose derivative of the formula (V)

where R1is benzoyl or

R2is hydrogen; and

R3is phenyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a variant of admixture extraction from composition containing extraneous matter and sucralose, which is used as a sweetener. One of the variants includes following stages: (a) first solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of another solvent, at least partially immiscible, in order to remove admixtures to the said second solvent; (b) second solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of the third solvent, at least partially immiscible, in order to transfer sucralose to the said third solvent; where stage (a) removes at least a part of admixtures to the second solvent; and stage (b) transports most of sucralose to the third solvent and detains most of admixtures in the first solvent.

EFFECT: efficient removal of admixtures from compositions.

34 cl, 4 tbl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: developed method of sucralose production using acyl-sucralose implies (a) adjustment of pH factor of specified supplied mixture to value ranged from 8.0 to 12.0 by alkali metal hydroxide addition; (b) buffer addition to specified base mixture in amount enough for specified pH factor stabilization within stated range over holding stage (c); (c) holding of specified base mixture at appropriate temperature over time period enough for effective transformation of specified acyl-sucralose compound into free sucralose; (d) reduction of specified pH factor of specified base mixture up to value from 4 to 8; (e) sucralose release from product of step (d) resulted thereby in released sucralose.

EFFECT: improved method of water deacylation procedure stabilization.

22 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: pharmaceutical technology.

SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.

EFFECT: improved preparing method, improved properties of composition.

24 cl, 4 tbl, 4 ex

The invention relates to medicine, more specifically to radiopharmaceuticals for diagnostic purposes, and may find application in positron emission tomography

The invention relates to the technology of 1,4 : 3,6-dianhydro-D-sorbitol (sorbed, isosorbide), which is an intermediate in the production of medicines on the basis of its mono - and dinitropropane, which is used as a vasodilator prolonged action in hypertension, angina and other cardiovascular diseases

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

The invention relates to compounds that are used as medicines, which have antiendotoxin activity, in particular analogs of lipid A

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.

EFFECT: creation of efficient method of gemcitabine hydrochloride purification.

5 cl, 1 tbl, 5 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.

EFFECT: creation of efficient method of gemcitabine hydrochloride purification.

5 cl, 1 tbl, 5 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: in derivatives of colchicine of general formula (I) X is oxygen or sulphur, particularly - to 3-O-β-D- xylopyronozyl-3-O-demethyltiocolchicine and 3-O-β-L- xylopyrano-zyl-3-O-demethyltiocolchicine.

EFFECT: efficient for preparation of miorelaxant medications, medications for treatment of inflammatory conditions, which influence muscular system, and antigout medications.

11 cl, 2 tbl, 6 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new non-steroidal anti-inflammatory compounds represented with the formula I: , where M is a macrolide subunit of the formula , D is a non-steroidal subunit, obtained from a non-steroidal anti-inflammatory drug, L is a connecting group with the formula X1-(CH2)m-Q-(CH2)n-X2, or their pharmaceutically permissible salts or separate diastereoisomer. Apart from that, this invention relates to the method of obtaining compounds of the formula I (versions), to the pharmaceutical composition on the basis of the compounds of formula I or their pharmaceutically permissible salts and also to the administration of formula I or their pharmaceutically permissible salts to obtain medicine (versions). The values of the substitutes R1-R6, A, B, E, U, Y, Z, W, S1, M, D, X1, X2, Q, m, are shown in the formula of the device.

EFFECT: obtaining new non-steroidal anti-inflammatory compounds.

11 cl, 1 tbl, 7 dwg, 23 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new non-steroidal anti-inflammatory compounds represented with the formula I: , where M is a macrolide subunit of the formula , D is a non-steroidal subunit, obtained from a non-steroidal anti-inflammatory drug, L is a connecting group with the formula X1-(CH2)m-Q-(CH2)n-X2, or their pharmaceutically permissible salts or separate diastereoisomer. Apart from that, this invention relates to the method of obtaining compounds of the formula I (versions), to the pharmaceutical composition on the basis of the compounds of formula I or their pharmaceutically permissible salts and also to the administration of formula I or their pharmaceutically permissible salts to obtain medicine (versions). The values of the substitutes R1-R6, A, B, E, U, Y, Z, W, S1, M, D, X1, X2, Q, m, are shown in the formula of the device.

EFFECT: obtaining new non-steroidal anti-inflammatory compounds.

11 cl, 1 tbl, 7 dwg, 23 ex

FIELD: medicine; pharmacology.

SUBSTANCE: crystal epirubicine hydrochloride of type II has diffraction pattern of X-ray powder scattering providing average diffraction angles (2θ) and relative intensities P(%), presented in the Table indicated below:

EFFECT: effective application of new crystal form for cancer treatment in people and animals.

6 cl, 7 dwg, 4 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to 5-amino-2 (β-D-galactopyranosyloxy)benzoic acid or 5-amino-2(α-D-galactopyranosyloxy)benzoic acid described by general formula [1]: or their pharmaceutically acceptable salt, pharmaceutical composition having therapeutic action for ulcerative colitis and based on this compound, as well as to therapeutic agent applied for ulcerative colitis including active component represented with 5-amino-2(β-D-galactopyranosyloxy)benzoic acid, 5-amino-2(α-D-galactopyranosyloxy)benzoic acid or 5-amino-2(β-D-glucopyranosyloxy)benzoic acid or their pharmaceutically acceptable salt. Connection under this invention can be effectively delivered to large intestine as exposure site, can be decomposed by intestine bacterial flora so that 5-aminosalicylic acid is formed in large intestine as active component.

EFFECT: new compounds possess useful biological properties.

3 cl, 1 tbl, 9 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula (I): , R1 represents C1-4-alkoxy C3-6cycloalkyl optionally substituted with atom of halogen, hydroxyl, trifluoromethyl, optionally substituted with halogen atom 5-6-member heterocyclyl, in which heteroatoms are selected from oxygen, optionally substituted with halogen atoms phenyl or optionally substituted with halogen atoms 5-6-member heteroaryl, in which heteroatoms are selected from nitrogen and/or sulfur; R2 represents hydrogen or trifluoromethyl; R3 represents hydrogen, optionally substituted with atom of halogen, C3-6cycloalkyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkyl phenyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkoxy heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, or optionally substituted with C1-4-alkyl 5-6-member heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen or oxygen, R4 and R5 independently represent hydrogen; X represents covalent bond or lower alkylene; X1 represents covalent bond or lower alkylene, Y represents covalent bond or lower alkylene, optionally substituted with hydroxy or cycloalkyl; and Z represents -C=C-, -R6C=CR7- or -CHR6CHR7-, where R6 and R7 in each position represent hydrogen or lower alkyl.

EFFECT: antilipolytic effect of compounds.

30 cl, 7 dwg, 31 ex

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