Taxane pentacyclic compound and antitumor agents based on thereof

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

 

The technical FIELD

The present invention relates to a derivative of Taxol, which can be administered orally and has antitumor activity.

PRIOR art

Taxol is a natural substance represented by the following chemical structural formula, which can be obtained in small quantities from the bark or other parts of Taxus brevifolia.

It is known that Taxol has antitumor activity, and it is believed that the mechanism of its action consists in inhibition of depolymerization of intercellular microrobot; therefore, expect that in the clinic it can be used as an antitumor agent with a mechanism of action different from conventional anticancer agents.

Taxol is still derived from natural sources and in very small quantities. However, reported Taxol derivatives, synthesized using the precursor of Taxol and 10-O-deacetylbaccatin III, represented by the following formula, which can be obtained from the leaves and other parts of plants of the family Taxus in relatively large quantities.

Among these compounds, attention is drawn to the connection (Taxotere, hereinafter referred to as "compound a"), having the structure before the purposes of the formula below, and having antitumor activity equal to or higher than the activity of Taxol and its study as an anticancer agent currently widely developed.

The authors of the present invention have reported that the compound obtained by the transformation of the hydroxyl group formed by the restoration of the 9 provisions of the ketone and hydroxyl group in position 10, in cyclic acatalog form has high antitumor activity (JP-A-9-12578, the designation "JP-A" means published, has not passed the examination of a patent application in Japan).

Taxol, Taxotere and connection, disclosed in JP-A-9-12578 are promising as anticancer agents. However, the compounds disclosed in the Examples application JP-A-9-12578, have the disadvantage from the point of view of their toxicity, and their effectiveness when administered orally unknown. For example, from the point of view of convenience for the patient during administration of the drug, as well as from the point of view of the health of the economy there is a need in the derived Taxol, which can be administered orally.

As a result of intensive studies to obtain a derivative of Taxol, which can provide high security for oral administration, while maintaining a high antitumor activity and reduce the Noah from the point of view of problems associated with toxicity, the authors of the present invention have conducted intensive studies and received the connection (hereinafter designated as "compound B")having the following formula and demonstrates high anti-tumor activity even when administered orally, for example in the test for antitumor activity in mice.

The problem of toxicity for this compound reduced in comparison with the compound disclosed in the Examples application JP-A-9-12578. However, failed to achieve guarantees its applicability when administered orally to man, as was found with the use of metabolic test in vitro using human liver microsomes, the metabolism of compounds in microsomes human liver runs very fast.

Description of the INVENTION

In order to inhibit modification of the connection due to its metabolism, the authors conducted a study of a new modification of the medicinal product and found that the compound, which introduces the substituent in the pyridine ring in position 13 side chain, bad undergoes metabolism in microsomes human liver and is able to provide the security required by oral administration, while maintaining antitumor activity and reduce problems with toxicity, which leads to Costigan the th purposes of the invention.

Accordingly, the invention relates to a compound represented by the following formula, or salts thereof, to medicaments comprising a compound with the following formula or its salt, as well as anticancer drug, which comprises a compound of the following formula or its salt.

The invention also includes an intermediate connection (hereinafter designated as "intermediate connection according to the invention")represented by the following formula is used to obtain the derivative of Taxol and its application.

The following formula, R1is dimethylaminomethyl or morpholinomethyl, and R2represents a halogen atom or alkoxy group containing from 1 to 6 carbon atoms. Preferred examples of R2include a methoxy group, a fluorine atom or a chlorine atom, more preferably a fluorine atom and a methoxy group.

Especially preferred is a compound represented by the following formula, namely:

(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxy-tax-11-EN-13-yl(2R, 3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate,

or it is salt.

Also, in the above-mentioned intermediate connection according to the invention R3is dimethylaminomethyl, morpholinomethyl or vinyl, R4represents a hydroxyl group which may have a protective group, and R5represents an alkoxy group containing from 1 to 6 carbon atoms, or a halogen atom. In addition, part of the dotted line between positions 6 and 7 of the partial patterns in the intermediate connection according to the invention, represented by the following formula

it means that communication in this part may be a double bond.

In the intermediate connection according to the present invention, examples of protective groups for R4include trialkylsilyl group, benzyl group, substituted benzyl group, 1-ethoxyethyl, benzyloxycarbonyl and 2,2,2-trichlorocarbanilide group. Preferred are trialkylsilyl group, such as triisopropylsilyl group, tert. butyldimethylsilyl group or triethylsilyl group and benzyl group, most preferred are triisopropylsilyl group and benzyl group.

The intermediate product to obtain a derivative of Taxol according to the present invention can be used by an optional selection in accordance with the final target product. For example, the La for obtaining compounds of the following formula

or its salts, it is desirable to use a compound of the following formula

(where R6is triisopropylsilyl group, tert. butyldimethylsilyloxy group, triethylsilyl group, or benzyl group) or its salt, the compound of the formula

(where R7is triisopropylsilyl group, tert. butyldimethylsilyloxy group, triethylsilyl group or benzyl group) or its salt or the compound of the following formula:

(where R8represents triisopropylsilyl, tert. butyldimethylsilyl, triethylsilyl or benzyl) or its salt.

The compound of the present invention may be in free form or in the form of an acid additive salt. Examples of the acid additive salts include salts of inorganic acids such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, or organic acid salts such as acetate, methanesulfonate, bansilalpet, toluensulfonate, citrate, maleate, fumarate, and lactate. It can also be in the form of MES, and examples of the solvent include water, methanol, ethanol, propanol, butanol, acetone, acetonitrile, benzene, toluene, tetrahydrofuran and N,N-dimethylformamide.

The connection is astasia the invention can be synthesized in accordance with the method, described in JP-A-9-12578, for example, by the following methods of synthesis. In this regard, the reaction can be carried out by protecting the substituting groups with in each case protective groups, however, the sequence of removing the protection is not so significant.

The method of Synthesis 1:

The compound (3) obtained by condensation of compound (1) with compound (2) in the presence of a base. Next, the protective group for the hydroxyl group of the thus obtained compound (3) is removed by formation of compound (4). Its terminal olefinic group in turn diol by the action of an oxidizing agent, such as N-methylmorpholin-N-oxide, in the presence of a catalyst of osmium tetroxide, and then subjected to oxidative cleavage by the action of periodate sodium or similar reagent with the formation of the aldehyde. This is followed by reduction reaction with the appropriate amine to obtain the compound (5).

The method of Synthesis 2:

Compound (7) obtained by condensation of compound (6) with compound (2) is similar to the Synthesis Method 1. Further, the compound (8) can be obtained by transformation of the terminal olefin group is similar to the Synthesis Method 1. Then the compound (9) obtained by recovery of the olefin with 6 - and 7-positions by hydrogenation, and then finally delete the Ute protective group of hydroxyl group, thus obtaining the compound (5).

The original substance (1) and (6) in the above-described Method of Synthesis of 1 can be synthesized in accordance with details described in JP-A-9-12578. The compound (2) can also be synthesized in accordance with the known method of synthesis for β -lactams described in the literature (see, for example, J. Org. hem., 61, 2664-2676 (1996)).

In the above synthesis methods R1, R2and R6defined as described below. As for the abbreviations, Vos denotes tertiary butoxycarbonyl group, AC represents acetyl group, and Bz denotes benzoyloxy group.

In addition, the treatment according to the invention can be used in the treatment of cancer based on its antitumor actions, and examples of interest for treatment include various types of cancer, such as lung cancer, gastrointestinal cancer, ovarian cancer, uterine cancer, breast cancer, liver cancer, head and neck cancer, blood cancer, kidney cancer and tumors of the testicles.

The compound of the present invention may be injected through a variety of injections, such as intravenous injection, intramuscular injection and subcutaneous injection, or by using various methods, such as oral or subcutaneous administration. Oral administration among these methods is desirable from the viewpoint of the effect, which is able described below. In the case of oral administration can be used any of the free compounds or salts.

When conducting a test using non-cancerous mice compound according to this invention showed no renal toxicity.

The applicability of the compounds according to the invention in the form of oral drugs can be predicted on the basis of tests in vitro using liver microsomes of human rights. In the case of oral administration the drug is dissolved in the gastrointestinal tract and undergoes metabolism in the digestive tract and liver and then enters the circulatory system. Accordingly, it is believed that the metabolism of drugs in the liver shows the effect on the expression efficiency of the medicines. In particular, predicted that the connection according to the invention and similar compounds undergo metabolism under the influence CYP3A, which is the enzyme distributed in microsome liver. Thus, the prediction of metabolism in tests in vitro using liver microsomes is important when considering the possible clinical application in practice. It was reported, for example, in Pharm. Tech. Japan, 13, 17-39, 1997, J. Pharmacol. Exp. Ther., 283, 46-58, 1997 that the predicted values of metabolism during in vitro testing using liver microsomes practically coincide with the values measured in clinical tests on humans. M is croome liver of man comes, for example, the company Xenotech LLC, and the measurement of metabolic rate may be based on the above log.

After measuring metabolic rate in microsome liver is possible to calculate the bioavailability of drugs as theoretical value (J. Pharmacol. Exp. Ther., 283, 46-58, 1997). Bioavailability is defined as the number and level of drug that reaches the circulatory system in relation to the number of entered drug (Pharmacokinetic Studies on Drug Development, edited by Yuichi Sugiyama, p.15, published by Yakuji Jino). In the case of oral administration, there are many obstacles to getting drugs into the blood circulation system, such as dissolution in the gastrointestinal tract, passing through the mucous membrane of the intestinal tract and metabolism in the intestinal tract and liver. Thus, it is considered that the range of changes in its final concentration in the blood, namely, the bioavailability, the individual becomes higher in comparison with the case of direct injection into the bloodstream. Hellriegel and others examined the extent of bioavailability and its individual changes (CV value) for 149 names of the various drugs available on the market, and said that between them there is a negative correlation (Clin. Pharmacol. Ther., 60, 601-607, 1996). Thus, it is known that the range of variability in bioavailability among individuals becomes larger at that time which I value bioavailability becomes smaller.

With regard to anticancer agents, they are administered in amounts almost close to the maximum tolerated dose, in order to enhance the reaction, so that therapeutic range and the range of toxicity become very close, this results in a narrowing of the safe range. Thus, it becomes difficult to use as an antitumor agent with a drug with a wide range of individual variability of bioavailability.

As for the compounds of the present invention, the rate of its metabolism in microsomes human liver was reduced, and theoretical value bioavailability of its unmodified form is also increased. Thus, it was predicted that the range of variability of the values of bioavailability of unchanged compounds for individuals will be small. Because of this effect it is possible to conduct oral administration of the compounds according to the invention from the point of view of safety in a larger range of security, as well as from the point of view of increasing the effectiveness of the medication. In this regard, theoretical value bioavailability of unchanged compounds preferably equal to 0.4 or higher, more preferably 0.7 or higher.

In addition, the applicability of the compounds according to the invention as preparations for oral call is to be placed can be predicted on the basis of a test bioavailability (BP) in monkeys. The metabolism of the compound (V) by liver microsomes of mouse and dog is slow, and the property of its oral absorption is really great. On the other hand, its metabolism under the action of liver microsomes monkey is fast, as in the case of microsomes human liver. In this case, the property of the oral absorption of the compound (C) for monkeys is low. On the other hand, the metabolism of compounds according to the invention under the action of liver microsomes monkey is slow as in the case of liver microsomes of mouse and dog. Thus, when the bioavailability (BP) was measured using monkeys to get confirmation improve absorption by oral administration via inhibition of the metabolism, it was confirmed that the oral absorption in monkeys was significantly superior to the compounds according to the invention compared with the data for the connection (In).

As for the method of producing the pharmaceutical composition of drugs and anticancer drugs, they can be obtained by selection of an appropriate pharmaceutical preparation based on the desired method of maintaining and using the commonly used methods of obtaining. Examples of dosage forms of the antitumor agent according to this invention for oral administration may include tablets, p. the Rosca, granules and capsules. Examples of other dosage forms include solutions, syrups, elixirs, and aqueous or oil suspensions. Desirable of the above are capsules, tablets and solutions. In the case of injection in the retrieval process can be used additives, such as stabilizers, antiseptic agents, and agents that promote solubilization. If the solution containing the mentioned auxiliary substances is transformed into a solid preparative form freeze-drying or other similar way, it can be used as a pharmaceutical product, which is dissolved before use.

Solutions, suspensions and emulsions can be represented as liquid preparations and process for their preparation may be additional agents, such as suspendresume agents and emulsifiers.

The connection according to this invention can be used for the treatment of cancer in mammals, especially humans, and in the case of the introduction of man it is advisable to enter it once a day and repeat at appropriate intervals.

With regard to dose, it is desirable to introduce the drug in the range from about 0.5 mg to 50 mg, preferably from about 1 mg to 20 mg, but 1 m2the surface area of the body.

The invention is described in detail in the following examples. In the description of examples will be used following the e reduction. The first denotes tert.-butoxycarbonyl group. AC represents acetyl group, Bz represents benzoyloxy group, and TIPS means triisopropylsilyl group.

BRIEF DESCRIPTION of DRAWINGS

The drawing is a graph showing changes over time of the amount of metabolite formed from the corresponding compounds.

The PREFERRED METHOD of carrying out the INVENTION

EXAMPLE 1

STAGE 1: (1S, 2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-methoxy-2-pyridyl)-2-triisopropylchlorosilane

300 mg of the sample (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-(2-propenyl-identix)tax-11-ene was dissolved in 10 ml of dry tetrahydrofuran, and the solution was mixed with 0.63 ml hexamethyldisilazide lithium (1M solution in tetrahydrofuran) at -60° and was stirred for 25 minutes. To the reaction mixture at the same temperature was added 5 ml of tetrahydrofuran containing 280 mg of (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone, and the mixture was stirred under ice cooling for 40 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate to separate the layers, the aqueous layer was AKST who was agarawala with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent hexane:ethyl acetate = 1:1 (V/V)), obtained 540 mg of the desired compound.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,89-0,95 (21 H, m), 1,32 (3H, s), 1,33-of 1.62 (3 H, m), of 1.41 (9 H, s)of 1.52 (3 H, s)of 1.65 (3 H, s), equal to 1.82 (3 H, s), 1,92 of-2.32 (3 H, m), 2.49 USD (3 H, s), 2,98 (1 H, d, J=4.9 Hz), 3,85 (3 H, s), 4,20 (1 H, d, J=7,4 Hz), 4,22 (1 H, d, J=6.8 Hz), 4,32 (1 H, d, J=8,3 Hz), 4.95 points (1 H, s), a total of 5.21 (1 H, d, J=5.8 Hz), 5,26-of 5.29 (2 H, m), 5,39-5,47 (3 H, m), to 5.57 (1 H, d, J=17.6 Hz), 5,96-6,02 (2 H, m), 6,11 (1 H, Tr.- shaped, J=8,3 Hz), to 7.15 (1 H, DD, J=2,4, 8,8 Hz),7,31 (1 H, d, J=8,8 Hz), 7,44 (2 H, t, J=7.8 Hz), 7,56 (1 H, t, J=7.8 Hz), 8,13 (2 H, d J=7.8 Hz), compared to 8.26 (1 H, d, J=3.0 Hz).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-2-hydroxy-3-(5-methoxy-2-pyridyl)propionate

530 mg of the compound obtained in stage 1, was dissolved in 10 ml of dry tetrahydrofuran under ice cooling was added 1.0 ml of tetrabutylammonium fluoride (1M solution in tetrahydrofuran)and the mixture was stirred at this temperature for 30 minutes. To the reaction mixture were added water and ethyl acetate to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed n is sasenum aqueous solution of sodium bicarbonate and saturated saline in this order, then was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent hexane:ethyl acetate = 1:1 (by volume)), received 410 mg of the desired compound.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s)of 1.43 (9 H, s)of 1.50 (3 H, s), 1,60 is 1.91 (3 H, m), of 1.64 (3 H, s)of 1.74 (3 H, S), At 1.91 (1 H, s), 2,04-of 2.16 (2 H, m), 2,32-is 2.37 (1 H, M), Of 2.34 (3 H, s), with 2.93 (1 H, d, J=5.3 Hz), 3,85 (3 H, s), 4,18 (1 H, d, J=7,3 Hz), 4,22 (1 H, d, J=8,3 Hz)to 4.33 (1 H, d, J=8,3 Hz), 4,79 (1 H, Shir. C.), is 4.85 (1 H, Shir. C.), to 4.92 (1 H, Shir. C.), 5,23 (1 H, d, J=5.8 Hz), from 5.29-and 5.30 (2 H, m), 5,46 (1 H, d, J=10.3 Hz), to 5.58 (1 H, d, J=17,1 Hz), 5,90 (1 H, d, J=9.7 Hz), 5,96-6.03 (2 H, m), 6.09 (1 H, Tr.-shaped, J=8,4 Hz), 7,22 (1 H, DD, J=2,4, 8,8 Hz), 7,34 (1 H, d, J=8,8 Hz), 7,47 (2 H, t, J=7.8 Hz), 7,60 (1 H, t, J=7.8 Hz), 8,13 (2 H, d, J=7.8 Hz), by 8.22 (1 H, d, J=2,4 Hz).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)utilizandose]tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-2-hydroxy-3-(5-methoxy-2-pyridyl)propionate

400 mg of the compound obtained in the previous phase 2, was dissolved in 5 ml of tetrahydrofuran, the solution was mixed with 5 ml acetone, 5 ml of water, 5.9 mg of osmium tetroxide and 270 mg of N-methylmorpholin-N-oxide, and stirred at room temperature for 4.5 hours. To the reaction mixture were added ethyl acetate and 10% aqueous sodium thiosulfate solution to separate the layers, and the aqueous layer was extracted with ethylacetophenone layers were combined washed saturated aqueous sodium bicarbonate and saturated saline in this order, then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in 5 ml of tetrahydrofuran, and then the solution was mixed with 5 ml methanol, 5 ml of water and 990 mg of metaperiodate sodium and stirred at room temperature for 1.5 hours. To the reaction mixture were added ethyl acetate and water to separate layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous salt solution, then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in 30 ml of ethanol, and then the solution was mixed with 0.2 ml of the research, of 0.13 ml of acetic acid and 140 mg of cyanoborohydride sodium and stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, ethyl acetate and water to separate layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent chloroform:methanol 50:1 (vol./vol.), got 220 mg require the constituent compounds.

Melting point: 160-161°

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.27 (3 H, s)of 1.43 (9 H, s)to 1.48 (3 H, s)to 1.60 (3 H, s)1,72 (3 H, s), 1,78-2,12 (6 H, m), 2,31-of 2.38 (1 H, m), of 2.34 (3 H, s), 2,58 of 2.68 (4 H, m), 2,71 (1 H, DD, J=5,4, 13,2 Hz), and 2.79 (1 H, DD, J=3,9, 13,2 Hz), with 2.93 (1 H, d, J=5.3 Hz), of 3.75 (4 H, t, J=4.9 Hz), 3,86 (3 H, s)of 4.12 (1 H, d, J=7,3 Hz), is 4.21 (1 H, d, J=8,3 Hz)to 4.33 (1 H, d, J=8,3 Hz), was 4.76 (1 H, Shir. C.), is 4.85 (1 H, Shir. C)to 4.92 (1 H, s), 5,04 (1 H, t, J=4.6 Hz), 5,23 (1 H, d, J=6.9 Hz), from 5.29 (1 H, d, J=8,8 Hz), 5,90 (1 H, d, J=9.3 Hz), 5,98 (1 H, d, J=4.9 Hz), between 6.08 (1 H, Tr.-shaped, J=8,3 Hz), 7,22 (1 H, DD, J=2,9, 8,8 Hz), 7,34 (1 H, d, J=8,8 Hz), 7,47 (2 H, t, J=7.8 Hz), 7,60 (1 H, t, J=7.8 Hz), 8,13 (2 H, d, J=7.8 Hz), by 8.22 (1 H, d, J=2,9 Hz).

Elemental analysis (for C49H65N3O15)

Calculated: 62,87; N 7,00; N 4,49

Received: From 62,66; N 7,08; N 4,28

EXAMPLE 2

STAGE 1: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-chloro-2-pyridyl)- 2-triisopropylchlorosilane

The specified connection was obtained by the same method, as in stage 1 of Example 1, except that used the (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-chloro-2-pyridyl)-3-triisopropylsilyl-2-azetidinone instead of (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,87-0,94 (21 H, m), 1.18 to 1.69 in (2 H, m)is 1.31 (3 H, s, of 1.41 (9 H, s)of 1.52 (3 H, s)of 1.65 (3 H, s), equal to 1.82 (3 H, s), 1,72-2,05 (2 H, m), 2,24-of 2.34 (2 H, m), 2,48 (3 H, s), of 2.97 (1 H, d, J=5.4 Hz), 4,19-to 4.23 (2 H, m)to 4.33 (1 H, d, J=7.8 Hz), 4.95 points (1 N with), to 5.21 (1 H, d, J=5.8 Hz), 5,27-5,31 (2 H, m), 5,42-5,47 (3 H, m), to 5.58 (1 H, d, J=17.5 Hz), 5,96-6,04 (2 H, m), 6,11 (1 H, t, J=8,8 Hz), 7,38 (1 H, d, J=8,3 Hz), 7,44 (2 H, t, J=7,3 Hz), EUR 7.57 (1 H, t, J=7,3 Hz), the 7.65 (1 H, DD, J=8,3 Hz, 2.5 Hz), 8,13 (2 H, d, J=7,3 Hz), 8,53 (1 H, d, J=2.5 Hz).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-chloro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 2 of Example 1, except that as the source was used the compound obtained in the previous phase 1.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s), 1,22-of 1.65 (2 H, m), USD 1.43 (9 H, s), for 1.49 (3 H, s)of 1.64 (3 H, s)of 1.74 (3 H, s), 1,75-of 2.09 (2 H, m), 2,30-2,39 (2 H, m), 2,33 (3 H, s)to 2.94 (1 H, d, J=4.9 Hz), 4,18 (1 H, d, J=at 5.3 Hz), 4,22 (1 H, d, J=8,3 Hz), 4,32 (1 H, d, J=8,3 Hz), br4.61 (1 H, Shir. C.), to 4.92 (2 H, m), of 5.24 (1 H, d, J=6.3 Hz), and 5.30 (1 H, d, J=6.8 Hz), are 5.36 (1 H, d, J=9.3 Hz), 5,46 (1 H, d, J=10.5 Hz), to 5.58 (1 H, d, J=17.5 Hz), by 5.87 (1 H, d, J=9.3 Hz), 5,96-6,05 (2 H, m), 6,11 (1 H, t, J=7.8 Hz), 7,39 (1 H, d, J=8,3 Hz), 7,47 (2 H, t, J=7,3 Hz), 7,60 (1 H, t, J=7,3 Hz), 7,69 (1 H, DD, J=8,3 Hz, 2.4 Hz), 8,12 (2 H, d, J=7,3 Hz), 8,51 (1 H, d, J=2,4 Hz).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)ethylidene-dioxy]tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-CHL is R-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 3 of Example 1, except that as the source was used the compound obtained in the previous phase 2.

Melting point: 146-150°

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s), 1,20-1,72 (2 H, m), USD 1.43 (9 H, s)to 1.48 (3 H, s), and 1.63 (3 H, s)of 1.73 (3 H, s), 1,75-2,03 (2 H, m), 2,33 (3 H, s), 2,30-of 2.38 (2 H, m), 2,59-2,69 (4 H, m), of 2.72 (1 H, DD, J=5,4, 13,2 Hz), and 2.79 (1 H, DD, J=3,9, 13,2 Hz), 2,92 (1 H, d, J=4.9 Hz), 3,74 (4 H, t, J=4.9 Hz), 4,12 (1 H, d, J=7.9 Hz), 4,22 (1 H, d, J=8,8 Hz), 4,32 (1 H, d, J=8,8 Hz), 4,59 (1 H, Shir. C.), 4,91 (2 H, m), of 5.05 (1 H, t, J=4.4 Hz), 5,24 (1 H, d, J=6.8 Hz), to 5.35 (1 H, d, J=9.3 Hz), by 5.87 (1 H, d, J = 9.8 Hz), of 5.99 (1 H, d, J = 4.9 Hz), 6,10 (1 H, t, J = 8.0 Hz), 7,39 (1 H, d, J = 8,3 Hz), 7,47 (2 H, t, J = 7,3 Hz), 7,60 (1 H, t, J = 7,3 Hz), 7,69 (1 H, DD, J = 8,3 Hz, 2.4 Hz), 8,12 (2 H, d, J = 7,3 Hz)and 8.50 (1 H, d, J = 2.5 Hz).

Elemental analysis (for C48H62lN3About14·H2O)

Calculated: 60,15; N. Of 6.73; N To 4.38; Cl 3,70

Received: From 60,15; N 6,74; N 4,20; Cl 3,63

EXAMPLE 3

STAGE 1: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-fluoro-2-pyridyl)-2-triisopropylchlorosilane

The specified connection was obtained by the same method, as in stage 1 of Example 1, except that used the (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-fluoro-2-pyrid the l)-3-triisopropylsilyl-2-azetidinone instead of (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,87 - 0,94 (21 H, m), 1,20 - 1,70 (2 H, m)is 1.31 (3 H, s)of 1.41 (9 H, s)of 1.52 (3 H, s)of 1.65 (3 H, s), 1,82 (ZN, C), a 1.75 - 2,07 (2 H, m), 2.26 and of - 2.32 (2 H, m), 2.49 USD (3 H, s), of 2.97 (1 H, d, J = 5.4 Hz), 4,19 - to 4.23 (2 H, m)to 4.33 (1 H, d, J = 8 Hz), 4,96 (1 H, s), a total of 5.21 (1 H, d, J = 5,9 Hz), 5,27 -5,32 (2 H, m), 5,43 - 5,49 (3 H, m), to 5.58 (1 H, d, J = 17.5 Hz), 5,96 - 6,04 (2 H, m), 6,12 (1 H, t, J = 8 Hz), of 7.36 -7,47 (4 H, m), EUR 7.57 (1 H, t, J = 7,3 Hz), 8,13 (2 H, d, J =7,3 Hz), 8,43 (1 H, d, J = 2,4 Hz).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 2 of Example 1, except that as the source was used the compound obtained in the previous phase 1.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.27 (3 H, s), 1,20 by 1.68 (2 H, m)of 1.44 (9 H, s), for 1.49 (3 H, s)of 1.64 (3 H, s)of 1.74 (3 H, s), 1,75 - 2,05 (2 H, m), 2,30 - 2,39 (2 H, m), of 2.34 (3 H, s), with 2.93 (1 H, d, J = 4.9 Hz), 4,18 (1 H, d, J = 6,8 Hz)to 4.23 (1 H, d, J = 8,3 Hz)to 4.33 (1 H, d, J = 8,3 Hz), to 4.62 (1 H, d, J = 2.5 Hz), 4,90 to 4.92 (2 H, m), of 5.24 (1 H, d, J = 5.8 Hz), and 5.30 (1 H, d, J = 6.8 Hz), lower than the 5.37 (1 H, d, J = 9.3 Hz), 5,46 (1 H, d, J = 10,2 Hz), to 5.58 (1 H, d, J= 17 Hz), 5,90 (1 H, d, J = 10,2 Hz), 5,96 - 6,05 (2 H, m), 6,10 (1 H, t, J = 7.8 Hz), 7,40 - 7,49 (4 H, m), 7,60 (1 H, t, J = 7,3 Hz)to 8.12 (2 H, d, J = 7,3 Hz), to 8.41 (1 H, s).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)ethylidene-dioxy]tax-11-EN-13-yl (2R,3S)-3(tert.-butoxycarbonylamino)-3-(5-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 3 of Example 1, except that as the source was used the compound obtained in the previous phase 2.

Melting point: 148-152°

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s), 1,20 was 1.69 (2 H, m), USD 1.43 (9 H, s)to 1.48 (3 H, s)of 1.62 (3 H, s)1,72 (3 H, s), 1,75 - 2,02 (2 H, m), 2,33 (3 H, s), 2,30 - 2,39 (2 H, m), 2,59 - 2,69 (4 H, m), 2,71 (1 H, DD, J = 5,4, 13,2 Hz), and 2.79 (1 H, DD, J = 3,9, 13,2 Hz), 2,92 (1 H, d, J = 4.9 Hz), 3,74 (4 H, t, J = 4.9 Hz), 4,12 (1 H, d, J = 7,3 Hz), 4,22 (1 H, d, J = 8,3 Hz), 4,32 (1 H, d, J = 8,3 Hz), 4,60 (1 H, Shir. C.), 4,90 to 4.92 (2 H, m), 5,04 (1 H, t, J = 4.9 Hz), 5,24 (1 H, d, J = 6.8 Hz), are 5.36 (1 H, d, J=9.3 Hz), of 5.89 (1 H, d, J = 9.8 Hz), of 5.99 (1 H, d, J = 4.9 Hz), 6,09 (1 H, t, J = 8.0 Hz), 7,42 - 7,49 (3 H, m), 7,60 (1 H, t, J = 7,3 Hz), 7,60 (1 H, t, J = 7,3 Hz)to 8.12 (2 H, d, J = 7,3 Hz), 8,40 (1 H, s).

Elemental analysis (for C48H62FN3O14·H2O)

Calculated: 61,19; N 6,85; N 4,46; F 2,02

Received: From 61,16; N 6,85; N 4,36; F 2,05

EXAMPLE 4

(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxy-tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-2-hydroxy-3-(5-methoxy-2-pyridyl)propionate

The specified connection was obtained by the same method, as in stage 3 of Example 1, except that as the source was used the compound obtained in stage 2 of Example 1, umesto the research used dimethylamine (2M solution in methanol).

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s)of 1.43 (9 H, s)to 1.48 (3 H, s)to 1.61 (3 H, s)of 1.73 (3 H, s)and 1.83 - of 1.97 (3 H, m), 2,04 - 2,12 (2 H, m), 2,31 - of 2.38 (2 H, m), of 2.34 (3 H, s), 2,38 (6 H, s), 2,64 -2,76 (2 H, m), with 2.93 (1 H, d, J = 4.9 Hz), 3,85 (3 H, s), 4,13 (1 H, d, J = 7,4 Hz), is 4.21 (1 H, d, J = 8,3 Hz)to 4.33 (1 H, d, J = 8,3 Hz), 4,84 (1 H, d, J = 2.4 Hz), to 4.92 (1 H, s), free 5.01 (1 H, t, J = 4.9 Hz), 5,24 (1 H, d, J = 6,8 Hz), from 5.29 (1 H, d, J=8,8 Hz), 5,91 (1 H, d, J = 9.3 Hz), of 5.99 (1 H, d, J = 5.4 Hz), between 6.08 (1 H, t, J = 7.8 Hz), 7.23 percent (1 H, DD, J = 3,0, 8,3 Hz), 7,34 (1 H, d, J = 8,8 Hz), 7,47 (2 H, t, J = 7.8 Hz), 7,60 (1 H, t, J = 7.8 Hz), 8,12 (2 H, d, J = 7.8 Hz), by 8.22 (1 H, d, J=3.0 Hz).

EXAMPLE 5

(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxy-tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 3 of Example 1, except that as the source was used the compound obtained in stage 2 of Example 3, and instead of the research used dimethylamine (2M solution in methanol).

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s), 1,20 - 1,70 (2 H, m), USD 1.43 (9 H, s)to 1.48 (3 H, s)of 1.62 (3 H, s)of 1.73 (3 H, s), 1.75 is for 2.01 (3 H, m), 2,33 (3 H, s), 2,38 (6 H, s), 2,32 - 2,39 (2 H, m)to 2.66 (1 H, DD, J = 5,4, 13,2 Hz)that is 2.74 (1 H, DD, J = 4,0, 13,2 Hz), with 2.93 (1 H, d, J = 4.9 Hz), 4,12 (1 H, d, J = 7,3 Hz), 4,22 (1 H, d, J=8,3 Hz), 4,32 (1 H, d, J = 8,3 Hz), 4,90 to 4.92 (2 H, m), 5,02 (1 H, t, J = 5.4 Hz), 5.25-inch (1 H, d, J = the 6.8 Hz), are 5.36 (1 H, d, J = 6.8 Hz), 5,90 1 H, d, J = 8,8 Hz), of 5.99 (1 H, d, J = 4.9 Hz), 6,09 (1 H, t, J = 8.1 Hz), 7,42 - 7,49 (4 H, m), 7,60 (1 H, t, J = 7,3 Hz)to 8.12 (2 H, d, J = 7,3 Hz), to 8.41 (1 H, s).

EXAMPLE 6

STAGE 1: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene]tax-11-EN-13-yl(2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-triisopropylchlorosilane

The specified connection was obtained by the same method, as in stage 1 of Example 1, except that as the source was used (3R,4S)-1-(tert.-butoxy-carbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyl-2-azetidinone instead of (3R,43)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,89 - 0,93 (21 H, m)of 1.28 (3 H, s)of 1.39 (9 H, s), and 1.54 (3 H, s)of 1.66 (3 H, s), equal to 1.82 (3 H, s), 1,61 - of 1.64 (3 H, m),1,89 is 1.96 (2 H, m), 2,33 - 2,39 (2 H, m), 2.49 USD (3 H, s), 2,98 (1 H, d, J = 4,8 Hz), 4,21 - to 4.23 (2 H, m), 4,36 (1 H, d, J = 7.8 Hz), 4,96 (2 H, Shir. C.), 5,20 (1 H, d, J = 5,9 Hz), 5,27 (1 H, d, J = 6.8 Hz), 5,46 (1 H, d, J = 9.8 Hz), to 5.58 (1 H, d, J = 17,1 Hz), 5,61 (1 H, d, J = 6.8 Hz), 5,96 - 6,03 (2 H, m), between 6.08 - 6,12 (2 H, m), 7,25 - 7,29 (1 H, m), 7,40 (1 H, t, J = 8,3 Hz), 7,47 (1 H, t, J = 7.8 Hz), to 7.59 (1 H, t, J=7.8 Hz), 8,16 (2 H, d, J = 7.8 Hz), 8,39 (1 H, d, J = 3,4 Hz).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl) -2-hydroxypropionate

The specified connection is% was obtained by the same method, as in stage 2 of Example 1, except that as the source was used the compound obtained in the previous phase 1.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.30 (3 H, s)of 1.41 (9 H, s)and 1.51 (3 H, s)of 1.65 (3 H, s), is 1.81 (3 H, s), 1,57 - to 1.63 (3 H, m), 1,89 - of 1.95 (2 H, m), 2,03 - 2,10 (1 H, m), 2.35mm (3 H, s), 2,43 - 2,49 (1 H, m), 2.95 points (1 H, d, J = 4,9 Hz), 4,20 (1 H, d, J = 7,4 Hz)to 4.23 (1 H, d, J = 8,8 Hz)to 4.33 (1 H, d, J = 8,3 Hz), and 4.68 (1 H, d, J=2.5 Hz), to 4.92 (1 H, s), of 5.24 (1 H, d, J = 6.4 Hz), 5,31 (1 H, d, J = 6.8 Hz), 5,46 (1 H, d, J = 9.8 Hz), to 5.58 (1 H, d, J = 17,1 Hz), the 5.65 (1 H, d, J = 18.3 Hz), 5,97 - 6,05 (2 H, m), 6,10 (1 H, t, J = 8,8 Hz), 6,21 (1 H, d, J = 8,3 Hz), 7.29 trend -7,32 (1 H, m), 7,43 - 7,49 (3 H, m), 7,60 (1 H, t, J = 7,3 Hz), 8,14 (2 H, d, J = 7,3 Hz), to 8.41 (1 H, d, J = 4,9 Hz).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)ethylidene-dioxy]tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 3 of Example 1, except that as the source was used the compound obtained in the previous phase 2.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.29 (3 H, s)of 1.40 (9 H, s), for 1.49 (3 H, s)to 1.61 (3 H, s)to 1.79 (3 H, s), 1.70 to 2,03 (5 H, m), 2,30 is 2.44 (2 H, m), 2.35mm (3 H, s), 2,61 - 2,65 (4 H, m), 2,70 - 2,82 (2 H, m)to 2.94 (1 H, d, J = 4,8 Hz), of 3.75 (4 H, t, J = 4.9 Hz), 4,14 (1 H, d, J = 7,3 Hz)to 4.23 (1 H, d, J = 8,3 Hz)to 4.33 (1 H, d, J= 7.8 Hz), of 4.67 (1 H, s)to 4.92 (1 H, s)of 5.05 (1 H, t, J =4.9 Hz), 5.25-inch (1 H, d, J = 7,3 Hz), the 5.65 (1 H, d, J = 7.8 Hz), of 5.99 (1 is, d, J = 5.4 Hz), 6,09 (1 H, t, J = 7.8 Hz), of 6.20 (1 H, d, J = 8,3 Hz), 7,29 - 7,33 (1 H, m), 7,43 - 7,49 (3 H, m), 7,60 (1 H, t, J = 7,3 Hz), 8,13 (2 H, d, J = 7,3 Hz), 8,40 (1 H, d, J = 4,9 Hz).

EXAMPLE 7

(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxy-tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 3 of Example 1, except that as the source was used the compound obtained in stage 2 of Example 6, and instead of the research used dimethylamine (2M solution in methanol).

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.29 (3 H, s)of 1.41 (9 H, s), for 1.49 (3 H, s), and 1.63 (3 H, s)to 1.79 (3 H, s), 1,86 - 2,08 (5 H, m), 2,32 - of 2.38 (2 H, m), of 2.34 (3 H, s), 2,38 (6 H, s)to 2.66 (1 H, DD, J = 5,4, to 13.6 Hz), a 2.75 (1 H, DD, J = 3,9, to 13.6 Hz), to 2.94 (1 H, d, J = 4.9 Hz), 4,14 (1 H, d, J = 6.9 Hz), 4,23 (1 H, d, J = 8,3 Hz)to 4.33 (1 H, d, J = 8,3 Hz), and 4.68 (1 H, d, J = 2,9 Hz), to 4.92 (1 H, s), 5,02 (1 H, t, J = 4.9 Hz), 5.25-inch (1 H, d, J = 6,8 Hz), the 5.65 (1 H, d, J = 8,3 Hz), 6,00 (1 H, d, J = 4.9 Hz), 6,09 (1 H, t, J = 7.8 Hz), 6,21 (1 H, d, J = 8,3 Hz), 7,28 - 7,33 (1 H, m), 7,43 -7,49 (3 H, m), 7,60 (1 H, t, J = 7,3 Hz), 8,14 (2 H, d, J = 7,3 Hz), to 8.40 (1 H, d, J = 4.4 Hz).

EXAMPLE 8

STAGE 1: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene]Dachshund-6,11-Dien-13-yl(2R, 3S)-3-(tert.-butoxycarbonylamino) -3- (5-methoxy-2-pyridyl)-2-treetop openserialport

300 mg of (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-(2-propenylidene)tax-6,11-diene was dissolved in 10 ml of dry tetrahydrofuran, and the solution was mixed with 0.63 ml hexamethyldisilazide lithium (1M solution in tetrahydrofuran) at -60° and was stirred for 20 minutes. To the reaction mixture at the same temperature was added 5 ml of tetrahydrofuran containing 280 mg of (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone, and the mixture was stirred under ice cooling for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent hexane:ethyl acetate = 5:1 (vol./vol.), received 530 mg of the desired compound.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,87 - 0,93 (21 H, m)of 1.29 (3 H, s)of 1.41 (9 H, s), and 1.54 (3 H, s), 1.69 in (3 H, s)of 1.75 (3 H, s), equal to 1.82 (1 H, s)to 2.29 (1 H, DD, J = 9,8, and 15.1 Hz), 2.40 a (1 H, DD, J = 8,8, 15.1 Hz), 2,53 (3 H, s), 3,13 (1 N, d, J = 5.8 Hz), 3,85 (3 H, s), Android 4.04 (1 H, d, J = 7,3 Hz), 4,30 (2 H, Shir. C.), the 4.90 (1 H, d, J = 3,9 Hz), 5,20 - 5,23 (2 H, m), 5,28 (1H, d, J = 9.8 Hz), 5,38 (1 H, s), 5,47 - 5,49 (2 H, m), the ceiling of 5.60 (1 H, d, J = 17.0 G is), 5,71 (1 H, DD, J = 4,4, 10,2 HZ), 5,96 - 6,06 (2 H, m), 6,09 - 6,14 (2 H, m), 7,16 (1 H, DD, J = 2,9, 8,3 Hz), 7,31 (1 H, d, J =8,3 Hz), 7,47 (2 H, t, J = 7.8 Hz), 7,58 (1 H, t, J = 7.8 Hz), 8,3 Hz), 7,47 (2 H, t, J = 7.8 Hz), 7,58 (1 H, t, J = 7.8 Hz), 8,14 (2 H, d, J = 7.8 Hz), compared to 8.26 (1 H, d, J = 2,9 Hz).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)ethylidene-dioxy]Dachshund-6,11-Dien-13-yl- (2R,3S)-3-(tert.-butoxycarbonyl-amino)-3-(5-methoxy-2-pyridyl)-2-triisopropylsilane-propionate

520 mg of the compound obtained above in stage 1, was dissolved in 5 ml of tetrahydrofuran, the solution was mixed with 5 ml acetone, 5 ml of water, 13 mg of osmium tetroxide and 300 mg N-methylmorpholin-N-oxide and stirred at room temperature for 7.5 hours. To the reaction mixture were added ethyl acetate and 10% aqueous sodium thiosulfate solution to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate solution and saturated saline solution in this order, then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in 5 ml of tetrahydrofuran, and then the solution was mixed with 5 ml methanol, 5 ml of water and 1.1 g of metaperiodate sodium, and stirred at room temperature for 1.5 hours. To the reaction mixture were added ethyl acetate and water to separate layers, and the aqueous layer was extracted with what acetate. The organic layers were combined, washed with saturated aqueous salt solution, then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in 30 ml of ethanol, and then the solution while cooling with ice blended from 0.22 ml of the research, 0.15 ml of acetic acid and 160 mg cyanoborohydride sodium, and stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, ethyl acetate and water to separate layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent hexane:ethyl acetate 3:2 (vol./vol.), received 290 mg of the desired compound

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,87 - 0,93 (21 H, m)of 1.28 (3 H, s)of 1.41 (9 H, s)of 1.53 (3 H, s)of 1.55 (3 H, s)of 1.73 (3 H, s)of 1.80 (1 H, s), and 2.26 (1 H, DD, J = 8,8, 15.1 Hz), 2,39 (1 H, DD, J = 9,8, and 15.1 Hz), 2,53 (3 H, s), 2,60 of 2.68 (4 H, m), is 2.74 (1 H, DD, J = 4,9, of 13.7 Hz), of 2.81 (1 H, DD, J = 4,9, of 13.7 Hz), 3,12 (1 H, d, J = 5.4 Hz), 3,76 (1 H, t, J = 4,8 Hz), 3,85 (3 H, s)to 3.99 (1 H, d, J = 7.9 Hz), 4,30 (2 H, s), 4,89 (1 H, d, J = 3,9 Hz), 5,02 (1 H, t, J = 3,9 Hz), 5,14 (1 H, d, J = 7,3 Hz), 5,27 (1 H, d, J=9.8 Hz), lower than the 5.37 (1 H, d, J = 1.5 Hz), vs. 5.47 (1 H, d, J = 9.8 Hz), 5,69 (1 H, DD, J = 3,9, and 10.5 Hz), 5,94 (1 H, d, J = 5.3 Hz), 6,07 - 6,13 (2 H, m), 7,16 (1 H, DD, = 2,9, 6.3 Hz), 7,30 (1 H, d, J = 6.3 Hz), 7,47 (2 H, t, J = 7.8 Hz), 7,58 (1 H, t, J=7.8 Hz), 8,15 (2 H, d, J = 7.8 Hz), compared to 8.26 (1 H, d, J = 2,9 Hz).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)ethylidene-dioxy]tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(5-methoxy-2-pyridyl)-2-triisopropylchlorosilane

235 mg of the compound obtained above in stage 2, was dissolved in 10 ml of ethanol, and the solution was mixed with 235 mg of the catalyst is 5% palladium on coal (wet) and was shaken for 10 hours under hydrogen pressure (392 kPa). After removal of catalyst by filtration, the filtrate was concentrated to obtain 230 mg of the desired compound.

1H-NMR (400 MHz, CDCl3, TMC) δ :

from 0.88 to 0.94 (21 H, m), of 1.30 (3 H, s)of 1.42 (9 H, s)of 1.50 (3 H, s)to 1.60 (3 H, s)to 1.79 (3 H, s), 1,84 - 2,30 (7 H, m)of 2.50 (3 H, s), 2,60 - 2,84 (4 H, m), 2,85 of 2.92 (2 H, m), 2.95 points (1 H, d, J = 4.4 Hz), of 3.80 (4 H, t, J = 4.4 Hz), 3,85 (3 H, s)to 4.17 (1 H, d, J = 7,3 Hz), 4,19 (1 H, d, J = 8.7 Hz), 4,33 (1 H, d, J = 8,3 Hz), 4,96 (1 H, s), 5,10 (1 H, Shir. C.), 5,22 is 5.28 (2 H, m), of 5.40 (1 H, s)of 5.48 (1 H, d, J = 10.3 Hz), 5,96 (1 H, d, J = 4.9 Hz), 6,10 (1 H, t, J = 8,3 Hz), 7,12 - 7,17 (1 H, m), 7,31 (1 H, d, J = 8,3 Hz), 7,45 (2 H, t, J = 7.8 Hz), EUR 7.57 (1 H, t, J = 7.8 Hz), 8,13 (2 H, d, J = 7.8 Hz), compared to 8.26 (1 H, d, J = 2,9 Hz).

STAGE 4: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-(morpholino)ethylidene-dioxy]tax-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-2-hydroxy-3-(5-methoxy-2-pyridyl)propionate

230 mg of the compound obtained above in stage 3, RA is worked in 5 ml of dry tetrahydrofuran, under ice cooling was added 0,43 ml of tetrabutylammonium fluoride (1M solution in tetrahydrofuran)and the mixture was stirred at this temperature for 30 minutes. To the reaction mixture were added a saturated brine and ethyl acetate to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate solution and saturated saline solution in this order, then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent chloroform:methanol = 50:1 (vol./vol.), then recrystallize from aqueous ethanol, obtained 110 mg of the desired compound. His analytical data coincided with those of the compound obtained in stage 3 of Example 1.

EXAMPLE 9

STAGE 1: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-6,11-Dien-13-yl (2R, 3S) -3- (tert.-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl)-2-triisopropylchlorosilane

The specified connection was obtained by the same method, as in stage 1 of Example 8, except that the source was used (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-fluoro-2-pyridyl)-3-triisopropylsilyl the STI-2-azetidinone instead of (3R, 4S)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,88 - 0,92 (21 H, m)of 1.33 (3 H, s)to 1.38 (9 H, s), and 1.56 (3 H, s)of 1.76 (3 H, s), 2,41 at 2.45 (2 H, m), of 2.51 (3 H, s), 3,14 (1 H, d, J = 5.8 Hz), 4,06 (1 H, d, J = 7,8 Hz)to 4.33 (2 H, s), the 4.90 (1 H, d, J = 4.4 Hz), 4,94 (1 H, d, J = 2.4 Hz), 5,19 with 5.22 (2 H, m), of 5.48 (1 H, d, J = 10.3 Hz), 5,58 - 5,64 (2 H, m), 5,70 (1 H, DD, J = 10,3, 4,4 Hz), 5,96 - 6,14 (5 H, m), 7,26 - 7,30 (1 H, m), 7,41 (1 H, t, J = 8,5 Hz), 7,49 (2 H, t, J = 7.5 Hz), to 7.59 (1 H, t, J = 7.5 Hz), 8,17 (2 H, d, J=7.5 Hz), 8,40 (1 H, d, J = 4.4 Hz).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxydec-6,11-Dien-13-yl (2R,3S)-3-(tert.-butoxy-carbylamine)-3-(3-fluoro-2-pyridyl)-2-triisopropylsilane-propionate

The specified connection was obtained by the same method, as in stage 2 of Example 8, except that the source was used the compound obtained in the previous stage, and instead of the research used dimethylamine (2M solution in methanol).

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 0.87 to 0.92 (21 H, m), 1,32 (3 H, s)to 1.38 (9 H, s)of 1.55 (3 H, s)of 1.57 (3 H, s)of 1.75 (3 H, s), 2,39 (6 H, s), 2,42 -2,45 (2 H, m), of 2.51 (3 H, s)to 2.66 (1 H, DD, J = 5,1, 13,2 Hz), is 2.74 (1 H, DD, J = 4,2, 13,2 Hz), 3,14 (1 H, d, J = 5.8 Hz), 4,01 (1 H, d, J = 7.9 Hz), 4,32 (2 H, s), 4,90 - 4,94 (2 H, m)5,00 (1 H, t, J = 4.9 Hz), 5,15 (1 H, d, J = 7.9 Hz), 5,63 (1 H, d, J = 9.8 Hz), 5,69 (1 H, DD, J = 9,8, 4,4 Hz), 5,95 (1 H, d, J = 5.8 Hz), 6,07 - 6,13 (3 H, m), 7,26 - 7,28 (1 H, m), 7,41 (1 H, t,J = 9,2 Hz), 7,49 (2 H, t, J = 7.5 Hz), to 7.59 (1 H, t, J = 7.5 Hz), 8,17 (2 H, d, J = 7.5 Hz), 8,40 (1 H, d, J = 4.4 Hz).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxydec-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonyl-amino)-3-(3-fluoro-2-pyridyl)-2-triisopropylchlorosilane

The specified connection was obtained by the same method, as in stage 3 of Example 8, except that the source was used the compound obtained in the previous phase 2.

1H-NMR (400 MHz, CDCl3, TMC) δ :

0,83 - 0,93 (21 H, m), of 1.35 (3 H, s)to 1.38 (9 H, s)of 1.52 (3 H, s), 1.56 to 2,07 (5 H, m), of 1.62 (3 H, s), is 1.81 (3 H, s), 2,34 is 2.43 (2 H, m), 2,38 (6 H, s), 2.49 USD (3 H, s)to 2.66 (1 H, DD, J = 5,4, 13,2 Hz)that is 2.74 (1 H, DD, J = 3,4, 13,2 Hz), 2,98 (1 H, d, J = 5.4 Hz), 4,17 (1 H, d, J = 7,3 Hz), 4,22 (1 H, d, J = 7.8 Hz), 4,36 (1 H, d, J = 8,3 Hz), 4,96 (2 H, s)5,00 (1 H, t, J = 4,8 Hz), with 5.22 (1 H, d, J = 7,3 Hz), the ceiling of 5.60 (1 H, d, J=8,8 Hz), 5,98 (1 H, d, J = 4.9 Hz), between 6.08 - 6,10 (2 H, m), 7,26-7,28 (1 H, m), 7,40 (1 H, t, J = 9,2 Hz), of 7.48 (2 H, t, J= 7.5 Hz), to 7.59 (1 H, t, J = 7.5 Hz), 8,16 (2 H, d, J = 7.5 Hz), to 8.40 (1 H, d, J = 3,9 Hz).

STAGE 4: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxydec-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonyl-amino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 4 of Example 8, except that the source was used the compound obtained in the previous the current stage 3. His analytical data coincided with those of the compound obtained in stage 3 of Example 7.

EXAMPLE 10

(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene]Dachshund-6,11-Dien-13-yl (2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 2 of Example 1, except that as the source was used the compound obtained in stage 1 of Example 9.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.29 (3 H, s)of 1.39 (9 H, s), and 1.54 (3 H, s)to 1.60 (3 H, s)of 1.74 (3 H, s), at 1.91 (1 H, s), 2,35 - 2,48 (2 H, m), is 2.41 (3 H, s), 3,11 (1 H, d, J = 5.4 Hz), 3,92 (1 H, Shir. C.), a 4.03 (1 H, d, J = 7,6 Hz), 4,27 (1 H, d, J = 8.1 Hz), 4,33 (1 H, d, J=8,2 Hz), of 4.67 (1 H, Shir. C.), to 4.87 (1 H, d, J = 4,1 Hz), 5,22 -5,25 (2 H, m), of 5.48 (1 H, d, J = 10,8 Hz), the ceiling of 5.60 (1 H, d, J = 17.3 Hz), 5,62 - 5,64 (1 H, m)5,69 (1 H, DD, J = 4,1, 10,3 Hz), 5,98 - 6,13 (4 H, m), 6,21 (1 H, d, J = 8,3 Hz), 7,29 -7,33 (1 H, m), 7,43 - 7,50 (3 H, m), 7,60 (1 H, t, J = 7,3 Hz), 8,15 (2 H, d, J=7,6 HZ), 8,39 (1H, d, J=4,6 Hz).

EXAMPLE 11

(1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxy-tax-6,11-Dien-13-yl (2R, 3S)-3- (tert.-butoxycarbonylamino) -3-(3-fluoro-2-pyridyl)-2-hydroxypropionate

The specified connection was obtained by the same method, as in stage 2 of Example 1, except that as the similar was used connection obtained in stage 2 of Example 9.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.28 (3 H, s)of 1.39 (9 H, s)of 1.52 (3 H, s)of 1.57 (3 H, s)1,72 (3 H, s)to 1.86 (1 H, s), 2,27 is 2.46 (2 H, m), 2,39 (6 H, s)to 2.41 (3 H, s), 2,69 (1 H, DD, J = 5,2, 13,2 Hz), and 2.79 (1 H, DD, J = 4.2, and 13,2 Hz), 3,11 (1 H, d, J = 5,9 Hz), 3,98 (1 H, d, J = 7,6 Hz), 4,28 (1 H, d, J = 8.1 Hz), 4,33 (1 H, d, J = 8,3 Hz), of 4.66 (1 H, d, J = 2.5 Hz), to 4.87 (1 H, d, J = 4,1 Hz), 5,02 (1 H, DD, J = 4.2, and 4.8 Hz), 5,17 (1 H, d, J = 7.8 Hz), 5,62 (1 H, d, J = 8.5 Hz), of 5.68 (1 H, DD, J = 4,1, 10,3 Hz), 5,96 (1 H, m), 6,10 (2 H, m), of 6.20 (1 H, d, J = 6.9 Hz), 7,27 - 7,60 (6 H, m), 8,15 (2 H, d, J = 7,3 Hz), 8,40 (1 H, d, J = 4,6 Hz).

EXAMPLE 12

STAGE 1: (1S, 2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-5,20-epoxy-1-hydroxy-9,10-(2-propenylidene)tax-6,11-Dien-13-yl (2R,3S)-2-benzyloxy-3-(tert.-butoxycarbonyl-amino)-3-(3-fluoro-2-pyridyl)propionate

The specified connection was obtained by the same method, as in stage 1 of Example 8, except that the source was used (3R,4S)-3-benzyloxy-1-(tert.-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-2-azetidinone instead of (3R,4S)-1-(tert.-butoxycarbonyl)-4-(5-methoxy-2-pyridyl)-3-triisopropylsilyl-2-azetidinone.

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.32 (3 H, s)of 1.39 (9 H, s), and 1.56 (3 H, s)to 1.59 (3 H, s), 1.77 in (3 H, s), of 1.85 (1 H, s), 2,31 (3 H, s), 2,39 (2 H, m), of 3.13 (1 H, d, J = 6,1 Hz), 4,07 (1 H, d, J = 7,6 Hz), 4,18 (1 H, d, J = 12,0 Hz), or 4.31 (3 H, m), and 4.68 (1 H, d, J = and 12.2 Hz), the 4.90 (1 H, d, J = 4, 2 Hz), 5,23 (2 H, t, J = 7,1 Hz), of 5.48 (1 H, d, J = 11,0 Hz), 5,59 (2 H, m), 5,70 (1 H, DD, J = 44, the 10.5 Hz), of 6.02 (1 H, m), 6,13 (2 H, d, J = 10,2 Hz), of 6.26 (1 H, d, J = 9.0 Hz), to 6.88 (2 H, d, J = 7,1 Hz), 7,19 (3 H, m), 7,29 (2 H, t, J = 6.8 Hz), 7,49 (2 H, t, J = 7.8 Hz), 7,60 (1 H, t, J = 7,3 Hz), 8,16 (2 H, d, J = 7,3 Hz), 8,42 (1 H, m).

STAGE 2: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxydec-6,11-Dien-13-yl (2R,3S)-2-benzyloxy-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)propionate

The specified connection was obtained by the same method, as in stage 2 of Example 8, except that the source was used the compound obtained in the previous phase 1, and instead the research used dimethylamine (2M solution in methanol).

1H-NMR (400 MHz, CDCl3, TMC) δ :

of 1.26 (3 H, s)of 1.39 (9 H, s), and 1.54 (3 H, s)of 1.57 (3 H, s)of 1.75 (3 H, s), equal to 1.82 (1 H, s), 2,31 (3 H, s), 2,36 -2,39 (2 H, m), 2,38 (6 H, s), 2,71 (1 H, DD, J = 5,2, 13,2 Hz), 2,77 (1 H, DD, J = 4,1, 13,2 Hz), 3,12 (1 H, d, J = 5.6 Hz), was 4.02 (1 H, d, J = 7.8 Hz), 4,19 (1 H, d, J = and 12.2 Hz), or 4.31 (2 H, m), 4,36 (1 H, d, J = 2,9 Hz), and 4.68 (1 H, d, J = a 12.7 Hz), 4,88 (1 H, d, J = 4,1 Hz), free 5.01 (1 H, t, J = 4,7 Hz), 5,16 (1 H, d, J = 7.8 Hz), the ceiling of 5.60 (1 H, d, J = 8,8 Hz), 5,69 (1 H, DD, J = 4.2, and 10.3 Hz), to 5.93 (1 H, d, J = 5.6 Hz), 6,11 (2 H, m), 6,23 (1 H, d, J = 9.3 Hz), to 6.88 (2 H, d, J = 6.6 Hz), 7,16 - 7,31 (5 H, m), of 7.48 (1 H, t, J = 7.8 Hz), to 7.59 (1 H, t, J = 7,3 Hz), 8,15 (2 H, DD, J = 1,5, 7,1 Hz), to 8.41 (1 H, d, J = 2,9 Hz).

STAGE 3: (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-Acetoxy-2-benzoyl-oxy-9,10-[(1S)-2-(dimethylamino)utilizandose]-5,20-epoxy-1-hydroxydec-11-EN-13-yl (2R,3S)-3-(tert.-butoxycarbonyl-amino)-3-(3-fluoro-2-pyridyl)--hydroxypropionate

The specified connection was obtained by the same method, as in stage 3 of Example 8, except that the source was used the compound obtained in the previous phase 2. His analytical data coincided with those of the compound obtained in stage 3 of Example 7,

EXAMPLE TEST 1

The mouse fibrosarcoma Meth And was subcutaneously transplanted mice (line name: Balb/c), and each of the compounds dissolved in a mixture of solvents - ethanol, tween 80 and 5% glucose (5:5:90 (vol./about.)) was administered by intravenous infusion over 6, 8 or 10 days (or just over 6 days) after transplantation. Each animal operated on on the 17th day to determine the weight of the tumor, platelet count and renal toxicity. Each group used six mice.

The antitumor effect was calculated by the following formula: {1-(weight of tumors in the group with the compound/weight of the tumor in the group with the solvent)} × 100

The platelet count was expressed as platelets in the group with the entered connection/platelets in the group with the solvent) } × 100

Renal toxicity was defined as "modified" in that case, when the anatomy watched this macroscopic change as wilting, or such a change, as the deposition of transparent droplets of the substance in the cytoplasm of the ochechnogo cylindrical cells on histological examination.

Table 1
ConnectionDose (mg/kg)The anti - tumor effect (%)The number of platelets (%)Monitoring of renal toxicity
Example 51 from JP-A-9-125781,5× 37537modified
Example 70 from JP-A-9-125780,98× 37855modified
Example 81 from JP-A-9-125782,2× 36258modified
Example 121 from JP-A-9-125780,43× 37557modified
The compound (B)

The compound (B)
32,4× 1a)

22,5× 1
83

69
142

124
not modified

-
(a): Three dead 6 experimental mice.

SAMPLE TEST 2

B16 Melanoma BL6 subcutaneously transplanted mice (C57BL/6), and after 4 days was administered to each of the connections. In the case of intravenous administration, the compound of the formula And was introduced after its dissolution in a solvent mixture of ethanol, tween 80 and 5% glucose (5:15:80 (vol./vol.), the compound of Example 7 after dilution of the mixture is the same solvent at a ratio of 5:5:90 (vol./vol.). In the case of oral administration, each of the compounds suspended in 0.5% aqueous solution of sodium salt of carboxymethyl cellulose. Every 2 or 3 days after injection was measured body weight, every animal operated on 15 days after transplantation for measuring the weight of the tumor. The antitumor effect was calculated by the following formula: {1-(weight of tumors in the group with the compound/weight of the tumor in the group with the solvent)} × 100

Each group contained six mice.

Table 2
 Dose (mg/kg)Route of administrationAntitumor effect (%)
The compound (A)180,0

600,0
Intravenous

Oral
95,7

6,2
The compound (B)20,0

13,3
Oral

Oral
97,4

90,5
Connection from11,9

7,9
Intravenous

Intravenous
95,5

91,5
Example 711,9

7,9
Oral

Oral
97,4

91,5

EXAMPLE TEST 3

METABOLISM IN MICROSOME P450 PERSON

Each of the test samples RA is tarali in a mixture of Aceto-nitrile/water (1:1 vol./about.) up to a concentration of 500 μm, and the solution was mixed with microsomes human liver (Xenotech LLC) and other components such as various coenzymes and buffer solutions, and allowed to undergo reaction metabolism at 37° C.

The reaction solution consisted of phosphate buffer (0,076 M; final concentration, the same will apply hereinafter), the test sample (10 μm), microsome human liver (1 mg/ml), glucose-6-phosphate (10 mm), glucose-6-phosphate dehydrogenase (1 unit/ml), magnesium chloride (4 mm) and recovered phosphate nicotinamide adenine dinucleotide (β -NADP, 1 mm), and 500 μl of solution was used in one reaction. In this case the reaction solution, except β -NADP, pre-incubated at 37° With 2 minutes, then the reaction was initiated by addition of an aqueous solution β -NADP (50 mm, 10 ál).

The reaction was stopped by adding 1 ml of ice-cold acetonitrile in 1, 2 or 5 minutes after the start of the reaction.

In this regard, the sample 0 minutes after start of the reaction was obtained by adding water instead of the aqueous solution β -NADP and immediately add 1 ml of acetonitrile. To each of these samples was added 100 μl of substance - internal standard, and the reaction solution was centrifuged for 15 minutes. The obtained supernatant was injected into a column for high performance liquid chromatography (HPLC) to measure the desired concentration of Varazze. The number decreased compared to the concentration at 0 minutes from the start of the reaction was taken as the resulting number of metabolites (nmol/mg protein). The amount of metabolite formed per 1 minute (constant speed metabolism: k (nmol/min/mg protein)) was calculated as the slope of a plot of the linear dependence of the amount of metabolite formed from the reaction time, calculated by the method of least squares.

From the thus obtained rate constants k metabolism (nmol/min/mg protein) was calculated for specific hepatic clearance (CLint) according to the following formula. CLint (ml/min/kg body weight) = k × (g liver)/(kg body weight) × (45 mg protein microsome assay)/(g liver), liver weight per 1 kg of body weight is 20 g

In addition, it was calculated the liver clearance (CLh) of values Clint in accordance with the model of ideal mixing (J. Pharmacol. Exp. Ther., 283, 46-58, 1997).

CLh (ml/min/kg body weight) = Q × Clint/(Q + Clint), where Q is the blood flow through the liver of a person, defined as 20 ml/min/kg

theoretical value bioavailability (F) was calculated from CLh according to the following formula: F = (1-CLh/Q).

In addition, theoretical value of the bioavailability of unchanged compound was calculated by the formula 1 - F.

Connection
Table 3
ExampleExampleExample
(B)137
Constant metabolic rate(nmol/min/mg protein)0,590,150,020,08
Clint(ml/min/kg)53,113,51,87,2
theoretical value of F for not modified connection0,270,600,920,74

The results are presented in drawing 1 and Table 1. Theoretical values of F unchanged form compounds according to the invention exceeded theoretical value of F 0,27 unmodified form of the control connection (the connection formulas), which means that the range of variation of bioavailability decreases, the separation of therapeutic range, and range of toxicity can be achieved more accurately and, therefore, possibly using oral administration.

EXAMPLE TEST 4

The compound of formula (V) or of Example 1 was injected monkey intravenously or orally as a single dose and measured the changes in its concentration in blood for calculating PPKo-∞. ACCo-∞mean area under the curve of concentration of drug in the blood in vremena period from the time of injection (0 h) to infinity, and it can be calculated in accordance with the method (rule of-line)described in Kiyoshi Yamaoka and Yusuke Tanigawara, Yakubutsu Sokudoron Nyumon (Pharmacokinetics), pages 116-117, moreover, the ratio of CPD oral introduction to CPD intravenously was calculated as oral VA. Test for compounds of formula (I) was carried out on different individuals of the same monkeys by intravenous or oral administration, as well as test for compounds of Example 7 was carried out on 4 monkeys of the same species with intravenous and oral administration to calculate the average value of CPD.

Animal: the female of Massa computer, the method of administration (compound of formula (In)) [intravenous] ethanol: tween 80: 5% glucose = 5:5:90, [oral] 0,1 N solution of Hcl, (compound of Example 7) [intravenous] 10% β -CyD-SBE7 (pH 3.5 in physiological solution), [oral] 40 mm acetate buffer (pH 4,0).

Table 4
  ACCo-∞(ng· h/ml) 
 Dose(mg/kg)IntravenousOralOral VA(%)
The compound (B)1,6394,128,17,1
Connection

Example 7
1,8/td> 993,8620,662,4

INDUSTRIAL APPLICABILITY

The connection according to the invention was superior in terms of its toxicity and showed no renal toxicity. The connection according to the invention showed high antitumor efficacy in mice when administered orally. Because the connection according to the invention has a high theoretical value of F for its unmodified form, the range of changes in bioavailability is reduced, and can be achieved separation therapeutic range and range of toxicity. The connection according to the invention showed excellent properties of absorption when administered orally to monkeys. Accordingly, the connection according to the invention can be used as an antitumor agent that can be administered orally.

1. Pyh connection taxane, represented by the following formula:

where R1is dimethylaminomethyl or morpholinomethyl, and R2represents a halogen atom or alkoxygroup having from 1 to 6 carbon atoms,

or its salt.

2. The compound or its salt according to claim 1, where R2represents a methoxy group or a fluorine atom.

3. Pyh connection taxane, represented by the following formula:

or its salt.

4. The drug with antitumor activity, which comprises the compound or its salt described in any one of claims 1 to 3.

5. The antitumor agent which comprises the compound or its salt described in any one of claims 1 to 3.

6. Pyh connection taxane, represented by the following formula:

where R3is dimethylaminomethyl, morpholinomethyl or vinyl, R4represents a hydroxyl group which may have a protective group, and R5represents a halogen atom or alkoxygroup containing from 1 to 6 carbon atoms, and a part of the dotted line between positions 6 and 7 partial structure represented by the following formula

it means that communication in this part may be a double bond,

or its salt.

7. The connection according to claim 6, represented by the following formula:

where R6represents triisopropylsilyl group, tert-butyldimethylsilyloxy group, triethylsilyl group or benzyl group,

or its salt.

8. The connection according to claim 6, represented by the following formula:

where R7is Soboh triisopropylsilyl group, tert-butyldimethylsilyloxy group, triethylsilyl group or benzyl group,

or its salt.

9. The connection according to claim 6, represented by the following formula:

where R8represents triisopropylsilyl group, tertiary butyldimethylsilyloxy group, triethylsilyl group or benzyl group,

or its salt.

10. The compound or its salt according to any one of p-9 to obtain the compound or its salt described in any one of claims 1 to 3.

11. The connection of claim 10, represented by the following formula:

where R6represents triisopropylsilyl group, tert-butyldimethylsilyloxy group, triethylsilyl group or benzyl group,

or its salt to obtain a compound represented by the following formula:

or its salts.

12. The connection of claim 10, represented by the following formula:

where R7represents triisopropylsilyl group, tert-butyldimethylsilyloxy group, triethylsilyl group or benzyl group,

or its salt to obtain a compound represented by the following formula:

salt.

13. The connection of claim 10, represented by the following formula:

where R8represents triisopropylsilyl group, tertiary butyldimethylsilyloxy group, triethylsilyl group or benzyl group,

or its salt to obtain a compound represented by the following formula:

or its salts.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.

EFFECT: valuable medicinal properties of compound and composition, improved treatment method.

16 cl, 2 dwg, 3 tbl

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 a method for producing 1,4:3,6-dianhydro-D-sorbitol, which is an intermediate in the production of lekarstvennyh drugs on the basis of its mono - or dinitropropane

The invention relates to a method for epoxidation prehiring of olefin, which includes the interaction prehiring of the olefin with oxygen source in the presence of salt catalyst

The invention relates to powder clarifier number sorbitol-xylitol-acetaline connections for clarification of a semicrystalline polyolefin resins and compositions based on it

The invention relates to a method of obtaining modified in the 16,17-position epothilones, according to which the protected position of 3.7 or unprotected epothilone a or b a) hydronaut double bond in position 16,17 or) double bond in position 16,17 spend epoxidation and, if necessary, the obtained epoxide reduced to the alcohol in position 16, to a method for epothilone-N-oxides, in which the protected position of 3.7 or unprotected epothilone And or transferred to N-oxide, the N-oxide optionally subjecting the reaction of Qatar; the method of obtaining modified in the C-19 position epothilones by metallizirovanaya in position C-19 secured or unsecured epothilone a or b, as well as to modified epothilones General formula I

The invention relates to new epothilone formula 1, where R=CH3N

The invention relates to new substituted pyrazolylborate General formula (I) in which R1-R6have the meanings given in the description of the invention

The invention relates to a technology for 1,4,3,6-dianhydro-D-sorbitol dinitrate, which is the substance of the medicinal product "nitrosorbid"

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

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

that elicits strong antitumor effect. Also, invention relates to intermediates substances, a method for preparing compound of the formula (I), a method for preparing 1,14-β-hydroxy-1,14-carbonate-baccatin III-derivatives substituted with isoserine residue at position 3 and to pharmaceutical composition based on compounds of the formula (I). Invention provides preparing new derivative of taxane that elicits higher activity and reduced toxicity as compared with paclitaxel.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.

10 cl, 7 tbl, 6 ex

The invention relates to new S-4 carbonate-bearing similarly to taxanes of formula 1 and their pharmaceutical salts:

where R denotes phenyl, isopropyl or tert.butyl; R1denotes-C(O)RZin which RZmeans (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-furyl and R2denotes CH3C(O)O-, and also to pharmaceutical compositions based on them and their use as protophobic agents to treat diseases of humans and animals

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to a new method of acylation of the hydroxyl group taxane, including processing taxane allermuir agent selected from the group consisting of anhydrides, dicarbonate, thiodicarb and isocyanate in the reaction mixture containing less than one equivalent of base for each equivalent taxane, preferably 1:1-1:100, with the formation of the C(10) acylated taxane

The invention relates to a new method of obtaining Taxol, its analogs and their intermediates, including the stage of protection of the hydroxy-group at C-7 position 9-dihydro-13-deacetylbaccatin III a suitable protecting group; oxidation of the hydroxy-group in position C-9; and attaching a suitable side chain at position C-13

The invention relates to a new method of obtaining paclitaxel - anticancer agent and intermediate products for its partial synthesis: the compound of formula (II)

< / BR>
where a represents a group

< / BR>
R1the protection group of the hydroxyl or hydrogen atom, and R2is a hydrogen atom,

and the compound of formula (III)

< / BR>
where each of the groups R4and R5- aryl, and each of the groups R6and R7- halogenated methyl

The invention relates to chemistry, in particular to pharmaceutical chemistry, and can be used for the production of anticancer drug

Derivatives taxane // 2188198

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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