Derivatives of taxane, methods for their preparing and pharmaceutical composition

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 present invention relates to a new similarly to taxanes, useful as a chemotherapeutic agent, pharmaceutical compositions containing them, and methods of producing derivatives of 14-β -hydroxy-1,14-carbonate-baccatin III and V, substituted in position 13 ezoterikovym balance.

Taxanes is one of the most important classes of anti-cancer drugs developed in recent years. Considerable effectiveness paclitaxel and its analogue docetaxel in the treatment of various tumors has focused research on the substances with antimicrotubule activity. However, taxanes are characterized by the specific mechanism of action, in which they stimulate the Assembly of microtubules and inhibit the depolymerization of tubulin.

The main disadvantages of the currently used taxan are: (a) the insolubility in water, mandating the use of specific media, which can cause reactions hypersensibility; (b) toxicity, which limits the dosage; (C) the development of mechanisms of resistance. Cellular resistance similarly to taxanes linked to MDR-phenotype ("multiple drug resistance"),caused by the carrier of P-glycoprotein by alterations in tubulin and by changes in the expression of apoptotic regulatory proteins.

The pursuit is as new active molecules, having a higher solubility and better tolerance, synthesized derivatives taxane 14β -hydroxy-10-deacetylbaccatin III and V.

Some derivatives of 14-hydroxyacetone III, substituted in position 13 isoprinosine residues are disclosed in U.S. patent 5705508, together with the way they are received.

It is now established that the compound of formula (I), derived 14-β -hydroxy-1,14-carbonatation V

has significant cytotoxic and anti-cancer activity and is able to overcome the resistance of cell lines expressing the MDR-phenotype.

The specified connection is different from the derivatives described in the above U.S. patent, the hydroxyl in position 7, which in this case is in the alpha configuration. 13-(N-Boc-β -isobutylphenyl)-14β -hydroxy-baccatin III - 1,14 carbonate, the corresponding derivative, referred to in U.S. patent No. 5705508 as SB-T-101131, can be used as a starting material for obtaining the compound (I).

In this case, the specified baccatin III derived or treated with DBU (diazobicyclo[5,4,0]-7-undecene) in methanol or THF (THF), or just leave in a solution of methylene chloride or chlorinated solvents in the presence of aliphatic alcohols type methanol, ethanol or propanol with the basic oxide is m aluminum on time, ranging from one hour to 14 days. The connection with the C-7 beta-configuration, convert (translate) at neutral or slightly mainly on the pH more stable alpha-isomer (derived baccatin V).

Alternatively, the compound (I) can be obtained in a way that also allows to obtain the corresponding C-7 beta-epimer.

This method (A) includes the following stages:

a) conversion of 14β -hydroxy-10-deacetylbaccatin III or V in triethylenediamine in position 7 derived;

b) obtaining 1,14-carbonate derived from the compound from step (a);

C) selective acetylation of 10-hydroxyl;

d) reaction of the product from step (C) with (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid;

e) cleavage of the protective groups triethylsilyl and dimethoxybenzidine from the product from step (d).

According to a preferred embodiment of method (A), triethylchlorosilane used as similarbuy agent at the stage (a), whereas 1,14-carbonate derived at stage (b) is obtained with the use of phosgene in toluene in the solution of 3:1 methylene chloride/pyridine in a nitrogen atmosphere. At the next stage (s) 14-β -hydroxy-10-deacetylbaccatin III or V 7-Tes-1,14-carbonate forms a salt with litigationrelated (LiHMDS) in anhydrous THF and thus get lithium salt of 10-hydroxy derivative, the cat is the ROI then acetimidoyl with acetylchloride. The reaction of condensation between 14-β -hydroxy-7-s-1,14-carbonate-bakatina III or V and (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid (stage (d)) is carried out in an anhydrous non-polar organic solvent, in the presence of a base and a condensing agent type dicyclohexylcarbodiimide (DCC).

As a result, at stage (e) triethylsilyl removed from pyridine fluoride in a solution of acetonitrile/pyridine in a nitrogen atmosphere, while dimethoxybenzidine group is removed in methylenchloride solvent, adding the methanol - Hcl, and then NaHCO3.

The sequence of stages described method can be swapped, getting the final product with almost comparable output. Specified alternative process (C) includes the following stages:

a') selective acetylation of the hydroxyl at C-10 of 14β -hydroxy-10-deacetylbaccatin III, or V;

b') receiving 1,14 carbonate derivative of the product from step (a');

with') similarobama hydroxyl at C-7 position;

d') reaction of the product from step (C') with (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid;

e') the removal of protective groups triethylsilyl and dimethoxybenzidine from the product from step (d).

The last method is concluded several advantages, such as the ability to obtain the desired synthon (1,14 here is the bonate di 7-s-baccatin III or V) without chromatographic cleanings essentially only the crystallization.

According to a preferred embodiment, selective acetylation stage (a') is carried out with acetic anhydride in the presence of salts of cerium, scandium, ytterbium, preferably l3·7 H2O, whereas the other stages are being performed, as indicated above.

The present invention also includes, as an intermediate product of the method of obtaining 14-β -hydroxy-1,14-carbonatation III or V, the following connections: 14β -hydroxyacetic III or V, 14-β -hydroxyacetone III or V 1,14 carbonate, 14β -hydroxy-7-s-10-deacetylbaccatin III or V, 14β -hydroxy-7-s-baccatin III or V, 1,14 carbonate 14β -hydroxy-7-s-baccatin III or V.

Another aspect of the invention concerns a method for obtaining (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid according to the following scheme:

SCHEME

This method includes the following stages:

a) protection of the amino group latinola Nose-group;

b) the transfer of N-Boc-L-leucinol N-Boc-L-leucinol;

c) obtaining lingering derived product from step (b);

d) converting longitundinal to the corresponding carboxylic acid;

e) formation of methyl ether carboxylic acids;

f) purification of complex methyl ester (2R,3S)-3-(N-is)amino-2-hydroxy-5-methylhexanoic acid;

g) condensation of the product from step (f) with 2,4-dimethoxybenzaldehyde-dimethyl-acetal;

h) transforming the complex methyl ester (4S,5R)-N-BOC-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid to the corresponding carboxylic acid.

According to a preferred embodiment, at the stage of (a) carry out the reaction latinola with BOC-anhydride, and then oxidized to the aldehyde in the solvent DMSO/CH2CL12using oxalicacid at a temperature below -60°, neutralizing the resulting acid with triethylamine, or oxidize it with sodium hypochlorite at a temperature of from -2 to -5°, Cyanhydrin at the stage (C) receive, replacing sulfo group of intermediate 1-hydroxy-2-(N-Boc)amino-4-methylmethanesulfonate cyanide ion, Cyanhydrin then hydrolized to the corresponding carboxylic acid in stage (d) by boiling under reflux in concentrated hydrochloric acid.

At stage (e), (2R/S,3S)-3-(N-BOC)amino-2-hydroxy-5-methylhexanoic acid is transformed into the corresponding methyl ester by the interaction with diazomethane in ether solution. At stage (f) diastereoisomer(2R,3S) purify by crystallization from cyclohexane or a mixture of hexane/toluene. Stage (g) is performed in THF in the presence of pyridine-p-toluensulfonate, removing the released methanol; after completion of the reaction, pyridine-p-tol is onsultant neutralized by bicarbonate. At stage (h) ester hydrolyzing in a mixture of methanol/water with potassium carbonate. The reaction mixture is then acidified and the finished product is extracted with methylene chloride.

The invention also includes (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid as an intermediate compound for the synthesis of baccatin III and V derivatives, substituted at the 13-position of N-Boc-β -isobutyronitrile balance.

New taxon of the present invention showed strong anti-cancer activity against malignant cells of breast, lung, ovary, colon, prostate, kidney, pancreas, and also against cells resistant to known anti-cancer drugs such as adriamycin, vinblastine and platinum derivatives.

Thus, the invention relates to pharmaceutical compositions comprising an effective amount of the compounds of this invention, together with pharmacologically acceptable carriers and excipients. In more detail, the composition can be formed into the form of tablets, powders, granules, capsules, injections, solutions, suppositories, emulsions, dispersions, etc. For intravenous mainly apply the mixture Chremophor L and ethanol, Polysorbate and ethanol, or liposomal composition, obtained from natural or synthetic phosphatidylcholine, or a mixture of natural phospholipids in prisutstvie and cholesterol; for oral administration it is better to prepare soft gelatin capsules in which the product is dissolved in Polysorbate, PEG (PEG) or in mixtures of him, optionally in the presence of phospholipids. The compound (I) can be entered people at concentrations from 50 to 500 mg/m2.

The following examples illustrate the invention in greater detail.

Example 1: Synthesis of 1,14-carbonate 13-(N-Boc-β -isobutyl-serinol)-14β -hydroxyacetone III

43,26 g 14β -hydroxy-deacetylbaccatin III together with 22.3 ml of N-methylimidazole was dissolved in 230 ml of DMF (DMF) in a 500 ml glass round-bottom flask; the solution was added 14 ml of triethylchlorosilane with vigorous stirring at room temperature for 1 hour. After the reaction, the reaction mixture was poured into 2 l of water with vigorous stirring. Formed abundant precipitate, which was left at 4° in the evening (at night). Then the precipitate was filtered, thoroughly rinsing with water, and then n-hexane. After drying in vacuum was received of 48.1 g of 7-s-10-deacetylbaccatin III (XII)containing a small percentage of 7,10-derived, and having the following chemical-physical characteristics:

1H NMR (Dl3, 200 MHz): δ (ppm)=0,55 (6H, t, J=7.8 Hz, 7-OTES CH2), were 0.94 (9H, q, J=7.8 Hz, 7-OTES CH3), of 1.18 (3H, s, SN3), of 1.20 (3H, s, SN3), or 1.77 (3H, s, SN3), 1,90 (1H, ddd, J=2,4, 10,8, 13,2 Hz, SNβ ), 2,12 (3H, d, J=1.6 Hz, SN3), 2,31 (3H, s, 4-OSON3), 2,48 (3H, ddd, J=14,3, 9,8, 6,5 Hz, C6Hα ), 2,73 (1H, d, J=5.5 Hz, HE), WITH 3.79 (1H, d, J=7,1 Hz, C3N)4,20 (1H, dd, J=1,0, 8,3 Hz, SNβ ), or 4.31 (1H, d, J=8.6 Hz, SNα ), 4,39 (1H, dd, J=6,4 and 10.7 Hz, SN), OF 4.77 (1H, d, J=5.8 Hz, CN), 4,94 (1H, dd, J=2,1, 9.7 Hz, (SN), OF 5.05 (1H, m, C13H), 5,13 (1H, d, J=1.9 Hz, CN), equal to 6.05 (1H, d, J=7,3 Hz, CN), 7,41-8,09 (5H, m, Ph),

Mass spectrum (NH3DEP/CI, positive ions): m/z 718(M+NH4)+, 100%], 701 [M+N)+, 39%].

The compound obtained was dissolved in 300 ml of a 3:1 mixture of methylene chloride/pyridine in a nitrogen atmosphere, this solution was added under stirring to a solution of phosgene (214 ml of a 1.9 M solution in toluene), pre-cooled at -10° C, keeping the temperature between -5 to -10° during the addition.

The reaction mixture was stirred for 30’, then was dissolved in 700 ml of saturated solution Panso3keeping the temperature of 2° With or below. The phases were separated and the organic phase is washed to remove the pyridine. The organic phase was dried over gS4and was evaporated to dryness. Received with 46.6 g of 7-Tes-l,14-carbonate 10-deacetylbaccatin III, which can be used directly for the following reaction.

31 g of compound dissolved in 250 ml of absolutely anhydrous THF, the solution was cooled to -50° C, was added 48 ml of 1M LiHMDS in for 2 minutes and was stirred for 20 minutes at the same temperature. Added 3.7 g of acetylchloride is for 40 minutes under stirring. The reaction temperature was allowed to rise to 0° continuing the stirring for 2 hours. After the interaction, the mixture was treated with saturated solution of NH4CL and diluted with ethyl acetate. The phases were separated and the aqueous solution was diluted with ethyl acetate to extract the product. The combined organic phases are washed with water, then dried over MgSO4and was evaporated to dryness. Received 33 g 14-β -hydroxy-7-s-1,14-carbonate-baccatin III contaminated with compounds of the preceding reactions. The connection chromatographically on silica gel, elwira clean the product with a mixture of 9:1 ethyl acetate/CH2CL2Received 30 g of the desired compound (XIII)having the following characteristics:

1H NMR (CDCl3, 200 MHz): δ (ppm) = 0,55 (6N, t, J=7.8 Hz, 7-OTES CH2), 0,95 (N, q, J=7.8 Hz, 7-OTES CH3), of 1.16 (3H, s, SN3), 1,32 (3H, s, SN3), or 1.77 (3H, s, SN3), a 1.88 (1H, ddd, J=2,4, 10,8, 13,2 Hz, SNβ ), of 2.21 (3H, d, J=1.6 Hz, SN3), are 2.19 (3H, s, 10-OSON3), 2,31 (3H, s, 4-OSON3), 2,48 (3H, ddd, J=14,3, 9,8, 6,5 Hz, C6Hα ), 2,73 (1H, d, J=5.5 Hz, HE), AND 3.72 (1H, d, J=7,1 Hz, CN), 4,20 (1H, d, J=8,3 Hz, SNβ ), or 4.31 (1H, d, J=8.6 Hz, C20Hα ), to 4.46 (1H, dd, J=6,4 and 10.7 Hz, SN), 4,79 (1H, d, J=5.8 Hz, CN), 4,94 (1H, dd, J=2,1, 9.7 Hz (SN), 5,02 (1H, m, SN), OF 5.05 (1H, m, SN), 6,09 (1H, d, J=7,3 Hz, CN), 7,41-8,09 (5H, m, Ph).

Mass spectrum (NH3DEP/CI, positive ions): m/z 759 [(M+NH4)+ , 19%], 743 [M+N)+, 100%].

20 g 14β -hydroxy-7-s-1,14-carbonate-baccatin III together with 300 ml of strictly anhydrous toluene were placed in a round bottom flask with a capacity of 1 l, were added 10 g of (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid, 2 g of N,N-dimethylaminopyridine (DMAP) and 9.5 g of dicyclohexylcarbodiimide (DCC)dissolved in CH3CL2. The reaction mixture is boiled under reflux for 3 hours, then cooled, the product of urea was besieged, and the mother liquor was washed with saturated solution of NaHCO3to remove unreacted acid and then diluted hydrochloric acid to remove (DMAP), and finally re-Panso3for neutralization. The organic phase was evaporated to dryness to obtain 41.5 g of product, which can be used directly in the next stage.

40 g of this compound was subjected to the removal of protection in two stages, removing the first s and then 2,4-dimethoxybenzaldehyde, 40 g of compound was dissolved in 100 ml of a mixture (80:100) acetonitrile/pyridine in a nitrogen atmosphere and allowed to cool at 0°; added 13 ml pyridine fluoride and was stirred for 24 hours. The solution was poured into 2 l of water, the product was filtered and dried in vacuum.

The residue was dissolved in 60 ml of methylene chloride and this solution was added 40 ml of 0.6 N. Hcl in methanol at strong paramasivan and at 0° C. the Reaction mixture was left for 2 hours under stirring, then diluted in 150 ml of methylene chloride and shaken with a solution Manso3bringing the pH to 6-7. The organic phase was evaporated to dryness and led the residue from acetone-hexane. After drying were obtained 16 g of 13-(N-Boc-β -isobutylphenyl)-14β -hydroxyacetic-1,14-carbonate having the following chemical-physical and spectral characteristics:

Formula: C44H57NO17.

Appearance: white powder.

Melting point: 245° C.

2

Table 2.

Chemical shifts (ppm)13With NMR in solution Dl3(50,308 MHz)
ppm, multipletnessppm, multipletness
9201,8 thousand cub.-s858,2-s
1’172,6-s3’51,2-d
4-AboutOch3170,5-s344,6-d
10-AboutOch3170,2-s1541,3-s
2-Ph164,3-s439,9-t
=O (BOC)155,8-s634,9-t
=O (carbonate)151,4-s(H3)3C Boc27,7-q
12139,4-s1725,5-q
11133,1-s1622,6-q
(IU)3(Vos)80,0-s4-CCAH322,0-q
583,8-d10-CCAH320,2-q
187,7-s5’24,3-d
480,0-s6’22,7-q
269,0-d7’21,6-q
2075,5-t1814,6-q
2’73,3-d199,8-q
771,2-dq-benzoyl127,5-s
1074,3-do-benzoyl129,5-d
1374,1-dm-benzoylof 128.6-d
1479,1-dp-benzoyl1337-d

Mass spectrum: (NH3DEP/CI, positive ions): m/z 889 [(MNH4)+], 832 [(MNH4-(CH3)3C)+], 772 [(MNH4-BocNH2)+]

(NH3DEP/CI, negative ions): (m/z) 871 (M-), 260 (side chain)

Infrared spectrum (KBR disc): 3521, 3321, 2971, 2953, 1826, 1762, 1706, 1526, 1366, 1238, 1165, 1072, 723 cm-1

UV spectrum (Meon): 231, 276 and 284 nm;

-E1%at 231 nm = 180,99

-E1%at 276 nm = 14,094

-E1%at 284 nm = 12,182

Example 2: Synthesis of 13-(N-Boc-β -isobutylamino)-14β -hydroxyacetic V 1,14 carbonate

5 g of 13-(N-Boc-β -isobutylamino)-14β -hydroxyacetic III 1,14-carbonate was dissolved in 500 ml of toluene in an argon atmosphere, fully deoxygenate the solution was added 80 mg of DBU (diazobicyclo[5,4,0]-7-undecene), and the reaction mixture is boiled under reflux for 1 hour in argon atmosphere. The solution was diluted with 100 ml ethyl acetate and washed with water. Evaporated organic phase to dryness, to obtain 4.5 g 1,14 carbonate 13-(N-BOC-β -isobutylamino)-14β -hydroxyacetone V, with the following chemical-physical and spectral characteristics:

Formula: C44H57NO17

Appearance: white powder

Melting point: 245°

Table 3.

Chemical shifts (ppm)1H NMR in rest the re D1 3(200 MHz)
nPpm, multipletness (Hz)NPpm, multipletness (Hz)
26,18 d (7,9)2’*4,75 d (8,6)
33,80 d (7,8)3’4,01 m
54,93 dd (7,8, 4,8)4 a1,25 m
62,23 m4'b1,48 m
73,76 mS’1,67 m
106,79 s6’0,99 d (6,4)
136,44 d (6,7)7’0,97 d (6,4)
144,88 d (7,0)4-EA2,58 s
161,29 s10-EA2,20 s
171,31 sVos1,37 s
181,87 d (1,5)o-benzoyl8,06 m
191,71 sm-benzoyl7,49 m
20of 4.38 sp-benzoylto 7.61 m
3’-NH*4,60 d (11,2)
* M which can be reversed

Table 4.

Chemical shifts (ppm)13With NMR in solution Dl3(50,308 MHz)
CPpm, multipletnessPpm, multipletness
9206,1 sIn58,2 s
1’173,1 s3’52,0 d
4-AboutOch3172,7 s340,4 d
10-AboutOch3169,3 s1541,5 s
2-OPh165,1 s4’40,6 t
=O (BOC)of 156.6 s635,2 t
=O (Carbonate)152,1 s(H3)3C28,4 q
(Boc)
12137, 6mm s1725,4 q
11134,0 s1622,4 q
(IU)3(Vos)§81, s 4-CCAH322,7 q
582,7 d10-CCAH318,6 q
188,5 s5’25,1 d
80,7 s6’23,4 q
269,9 d7’20,9 q
2077,2 t18^15,2 q

Table 4.

Chemical shifts (ppm)13With NMR in solution Dl3(50,308 MHz)
2’°74,6 d19^16,2 q
77,6 dq-benzoyl128,3 s
10°74,2 do-benzoyl130,2 d
13°76,0 dm-benzoyl128,2 d
1479,9 dp-benzoylRUR 134.4 d
*, § , ° , ^ = can be reversed

Mass spectrum (TSP+): (m/z 872 (MN+); 816 (MN+-(CH3)2C=CH2); 772 (816-CO2); 756 (816-Asón); 712 (772-Asón)

Infrared spectrum (KBr disc): 3450, 2963, 1813, 1740, 1702, 1247, 1091,710 cm -1

UV spectrum (Meon): 200 e 230 nm

-E1%at 200 nm = 370,9

-E1%at 230 nm = 193,2

Example 3: Receive (4S,5R)-N-Boc-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid.

Obtain N-Boc-L-leucinol (III):

of 46.8 g L-leucinol II (400 mmol) was dissolved in 300 ml of CH2Cl12in a 2 l three-neck round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel. Then to mix the solution was added drop by drop at room temperature a solution of BOC-anhydride (87,2 g, 400 mmol) in CH2Cll2(100 ml) for 90 minutes adding the first 25% of the BOC-anhydride, the interaction was exothermic, reached 20-30° forming a suspension, which became clear after stirring at room temperature for three hours. Everything was left at room temperature overnight. The solvent was evaporated in high vacuum to obtain the desired product as a thick oil in quantitative yield (87 g). The product is then processed without further cleaning.

Obtain N-Boc-L-leucinol (IV)

In the solution oxalicacid (26,274 ml, 300 mmol) in 130 ml of methylene chloride, pre-cooled at-60/-65° C, was slowly added DMSO (28.4 ml, 400 mmol).

The solution becomes transparent after adding DMSO. After 20 min of stirring at the same temp is the temperature of the reaction mixture was treated with a solution of the alcohol III (43,7 g, 200 mmol) in CH2Cl2(200 ml) for 25 min, maintaining the temperature below -60° C. During the addition of alcohol, the reaction mixture became dull and formed a white precipitate. After 20-25 min of stirring at the same temperature was added drop by drop a solution of triethylamine (112 ml, 800 mmol) in CH2Cl2(100 ml) for 40 min, keeping the temperature between -68 and -62° C. the Reaction mixture was then stirred at a temperature between -60 and -65° in the next 50 minutes TLC of the reaction mixture was carried out using a mixture of 8% methanol in CH2Cl2because the eluent did not find the original product.

The cold solution is then poured into 800 ml of ice-cold solution containing 68 g (0.5 mol) KHSO4. The organic layer was separated and the aqueous phase was extracted with CH2Cl2(100 ml). The combined organic phases are washed with aqueous KHSO4(5%, 1× 200 ml), saturated salt solution (100 ml, 50 ml) and evaporated to half volume (≈ 250 ml). Specified substance was used directly in the next stage.

The aldehyde (V) bisulphite derivative

Methylenechloride solution of the aldehyde (IV) in a 2 l three-neck round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel, were treated for 10 min at -5° With a solution of sodium bisulfite (41.7 g, 400 mmol) in water (200 ml) and then H-Bu4 NKSO4(678 mg, 2 mmol). The solution was cooled to -5° C. the Reaction mixture was stirred at a temperature of from -5 to 0° C for 5-6 hours and then overnight at room temperature. The aqueous phase containing the composition V was separated and washed with CH2Cl2(2× 20 ml).

(2-cyano-3-(N-BOC)-amino-S-methylhexane (VI)

In the above-mentioned aqueous solution (≈ 250 ml) was added CH2CL2(120 ml) and the reaction mixture was cooled to 0-5° in a bath with ice. Then added solid KCN (15 g, 230 mmol) to the reaction mixture, and the solution was stirred at room temperature overnight. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with brine (1× 50 ml), dried over gSO4and evaporated to obtain the product as a colourless viscous liquid (43 g). The product has [α ]D51,11 (C=2, Meon) and is a mixture of VI 2(R),3(S) 2(S),3(S) derived a ratio of about 2:1. The output is 89% compared to the original L-latinoam.

(2RS,3S)-3-amino-2-hydroxy-5-methylhexanoic acid (VII)

A mixture of the above crude nitrile VI (43 g) was treated with 150 ml of concentrated Hcl (37%) (150 ml) and boiled under reflux during the night to obtain the crude acid VII*. Excess hydrochloric acid was removed on rotormichael and the residue was evaporated with water (100 ml) to remove Hcl. Then the residue was dissolved in 150 ml of water was added 100 ml of acetone, was treated with 33 ml of 6.25 M NaOH solution, bringing the pH to 5. An additional amount of acetone (500 ml) was added to the solution, which was left in the evening at 4° C. the Precipitate was then filtered off, washed with a solid cake on the filter with acetone and dried in vacuum to obtain the crude acid VII (6.5 g)containing a mixture of 2(R), 3(S) 2(S), 3(S) derivatives of compound VI in a ratio of about 3:1.

The filtrate was evaporated and added water to bring the solution volume to 75 ml

Then acetone (1 l) was added to the solution, which was left over night at 4° in the refrigerator. The precipitate was filtered and the solid cake on the filter was washed with acetone and dried in vacuum to obtain an additional amount of product (18 g)containing solid NaCl and a mixture of 2(R), 3(S) 2(S), 3(S) derivatives VII in the ratio of about 1:1.

The extracted first product VII (22,5 g) was heated in water (120 ml), not receiving complete dissolution, then cooled on ice and filtered to obtain 12.5 g of the acid VII, still contaminated with approximately 10% of the undesired 2(R), 3(S) derived VII. The product was dried and mixed with the aforementioned 1:1 mixture of crystals of the second collection (total 27 g).

(2RS,3S)-3-(N-Boc)amino-2-hydroxy-5-methylhexanoic acid (VIII)

(A) the Crude acid VI 2(R), 3(S), approximately 90% is istoty (2.5 g; and 77.6 mmol), was dissolved in a mixture of 1:1 water-THF (80 ml), then triethylamine (13.5 ml) and then the BOC-anhydride (18.5 g; 85 mmol) was added to the reaction mixture, the whole solution was stirred for 40 hours at room temperature. The solvent was evaporated on a rotary evaporator, was added 60 ml of water and 60 ml of ethyl acetate, continuing the stirring. The aqueous phase was separated and was extracted with ethyl acetate (30 ml). The combined organic phase was extracted with 10% aqueous sodium carbonate solution (30 ml, 20 ml). The basic extract was then combined with the aqueous phase was acidified with 2 M hydrochloric acid (≈ 55 ml)to bring the pH of the solution to 2. Acid VIII was then extracted from the aqueous phase with ethyl acetate (3× 40 ml) and heteroglossia extracts were washed with water (20 ml), dried (MgSO4) and evaporated to get the crude VIII Re-derived in the form of syrup (20 g, 99%).

(B) the Crude acid VII 2R, 3S, with a purity of about 50%, contaminated with Sodium chloride (27 g), was dissolved in a mixture of 1:1 water-dioxane (120 ml). Then was added triethylamine (20 ml) to the reaction mixture, followed by BOC anhydride (26,15 g, 120 mmol). The solution was stirred for 40 hours at room temperature. The solvent was evaporated in a rotary evaporator, water and ethyl acetate (100 ml) was added to the residue, continuing the stirring for several minutes. The organic phase was separated and was extracted with 10%aqueous sodium carbonate solution (45 ml, 30 ml). Extracts of sodium carbonate were then combined with the aqueous phase acidified with 1 M hydrochloric acid (≈ 165 ml) and extracted with ethyl acetate (3× 60 ml)and then washed with water (30 ml), dried (gSO4) and evaporated to get the crude VII Vos in the form of syrup (16 g), consisting of a mixture of 2R, 3S and 2S, 3S isomers in a 1:1 ratio.

Methyl ester (2R,3S)-3-(N-BOC)amino-2-hydroxy-5-methylhexanoic acid (IX)

Diazomethane was obtained from disordered, following the method described so-CALLED. Black [Aldrichimica Acta, 16, 3 (1983)].

(A) a Solution of the crude acid VIII (20 g, at 56.6 mmol) in CH2Cl2(75 ml) was slowly added to a cold ethereal solution of diazomethane (77 mmol) and the mixture was left for two hours in an ice bath. The color of the solution at this stage was white, thus indicating that a large part of diazomethane adsorbed. Then the solution is evaporated and the residue was led from a mixture of toluene (20 ml) and hexane (70 ml). After cooling overnight in the refrigerator at 4° C, crystals of pure IXA 2R, 3S derivative was collected by filtration. The yield was 15, Uterine solutions were given approximately 5 g of a mixture of isomers in a ratio of 1:1.

(B) Applying the same method, 1:1 mixture of the acid VIII (16 g) was converted into 1:1 mixture of IXA and IXB esters.

Added material from the mother solution (5 g with study is A), material were combined and separated on a chromatographic column using hexane-ethyl acetate as eluent (9:1 to 7:3). The ninhydrin was used as the developer for TLC plates, non-Polar Rf connection 0,75 (hexanitrate: 7:3) was identified as the desired ether IXA (2R,3S), which was recrystallized from cyclohexane to obtain IXA in the form of colorless needles (8 g) t° pl. 95-96°, [α ]D72,4° (C=l, Meon).

Polar connection Rf of 0.5 (hexane-ethyl acetate 7:3) identified as IXB (2S,3S) and recrystallized from cyclohexane to obtain 10 g IXB in the form of colorless needles.

2,4-dimethoxybenzaldehyde

A mixture of 2,4-dimethoxybenzaldehyde (41,25 g, 0.25 mol), anhydrous triethylorthoformate (50 ml) and ammonium nitrate (2 g dissolved in 20 ml methanol) was boiled under reflux for 6 hours (1H NMR of the reaction mixture showed 65-70% conversion). First, the hot reaction mixture was a clear solution, but because the interaction continued, dropped a solid residue. Added the second part of anhydrous triethylorthoformate (20 ml), and part of the methanol drove away.

When the temperature of the reaction mixture reached 95-100° s With all the residue in the flask was dissolved. The solution was cooled to room temperature and was added dehydrated PA2CO3(5 g), stirring 30 minutes After the according solution was filtered and the residue was distilled by fractional distillation in vacuum at 0.25 mm Hg The first fraction at low temperature consisted mainly of excess triethylorthoformate, and the second fraction, which was converted into the form of a colorless oil at 175-180° represented the desired acetal. Yield: 37 g (70%).

Methyl ester of (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid (X)

In the complex solution of methyl ester (2R,3S)-3-(N-BOC)amino-2-hydroxy-5-methylhexanoic acid (IXA) (34,375 g, 125 mmol) in anhydrous THF (150 ml) was added distilled 2,4-dimethoxybenzaldehyde, dimethylacetal (30 g, 142 mmol) and then pyridine-p-toluensulfonate (Ru. s; 400 mg).

The solution was heated at moderate boiling in a 500 ml three-neck flask with reflux condenser equipped with a nozzle Dean-stark. After approximately 6 hours boiling under reflux, removing about 60 ml of THF containing methanol, obtained in the course of the reaction. The sample was subjected to1H NMR analysis (in CDCL3).

Peak at δ =1,41 ppm disappeared (1), and a new peak appeared when the δ =1,24 ppm for the protected methyl ester (2). After 6 hours boiling under reflux transformation was about 70-75%.

Added a new portion anhydrous THF (50 ml), then 2,4-dimethoxybenzaldehyde (5.0 g; 24 mmol). The reaction mixture was heated under reflux for a further 2.5 hours, during which it was removed is about 50 ml of THF, using the nozzle Dean-stark. Subsequent1H NMR analysis showed complete conversion of the starting material.

In the reaction mixture were added saturated aqueous solution of NaHCO3(15 ml) and the mixture was stirred for 15 minutes to neutralize Py. The Tos. Then was added tert-butyl methyl ether (85 ml) and water (15 ml) and the separated organic phase. The aqueous phase was extracted with tert-butylmethylamine ether (20 ml) and the combined organic phases were washed with water (30 ml) and evaporated to obtain a residue (66 g) of the crude product X.

Hydrolysis of ester X to obtain the acid XI

The crude ester X (22 g, 42 mmol) was dissolved in 100 ml of methanol and was added water (50 ml)containing 8.7 g of potassium carbonate. After stirring overnight at room temperature, it was considered that the reaction is complete when the control TLC (toluene-ethyl acetate: 4,5:1). TLC analysis confirmed1H NMR studies, checking the disappearance of the peak of the methyl ester.

The methanol was evaporated at a temperature not exceeding 40° C in vacuum (about 60 g of residue) and to the residue was added water (150 ml). The aqueous suspension was extracted with ethyl acetate (5× 50 ml)to remove excess benzaldehyde and benzaldehydes. To the aqueous phase was added 90 ml of methylene chloride, and the mixture was cooled in an ice bath, and a two-phase system processed approximately is about 125 ml of 1 M NaHS 4(pH 3) with vigorous stirring. The phases were separated and the aqueous phase was extracted with methylene chloride (75 ml). United methylenechloride extracts were washed with water (30 ml), brine (30 ml) and dried over gSO4. Then the solution was kept at -60° C. the Yield of the final product in the form of a colorless solid was 16 g, about 93%, relative to the original product.

Example 4: Obtaining 14β -hydroxy-7-s baccatin III 1.4 carbonate

To a solution of 11.2 g 10-deazetil-14-hydroxyacetic III in 50 ml of dry tetrahydrofuran was added to 0.72 g l3·7 H2Oh and 7.3 ml of acetic anhydride. The reaction mixture was stirred at room temperature for 5 hours, during which time the mixture became homogeneous. Added 10 g of ice, and all was stirred for 1 hour. The tetrahydrofuran is evaporated in vacuo and the residue was dissolved in 200 ml of H2O. the Precipitate was filtered and dried under vacuum in the presence of P2O5: the product has led from ethyl acetate, to obtain 10 g of 14-hydroxyacetone III, with the following characteristics:

TPL: 236-8° C; IR (KBR): 3474, 1739, 1400, 1240, 1090, 1049 cm-1.

1H NMR (CDCl3, 200 MHz); 8,07 (d, J=8 Hz, Bz)of 7.55 (d, J=8 Hz, Bz), 7,44 (t, J=8 Hz, Bz)of 6.31 (s, H-10), 5,80 (d, J=7 Hz, H-2), equal to 4.97 (br d, J=8 Hz, H-5), to 4.73 (br, d, J=4 Hz, H-13), to 4.41 (m, H-7), 4,24 (d, J=4 Hz, H-14), 4,20 (d, J=7 Hz, H-20a), 4,06 (d, J=7 is C, H-20b), 3,89 (J=0 Hz, H-3), to 2.29 (s, SLA), 2,22 (s, Oac), 2,04 (s, H-18), of 1.66 (s, H-19), 1,25, 1,11 (S, H-16 and H-17).

In chetyrehosnuju flask equipped with stirrer, dropping funnel, thermometer and a partial condenser hot irrigation, cooled to -12° With, put 52,8 ml of a 1.9 M solution of phosgene in toluene. In this solution drop by drop) was added 11.6 g 14-hydroxyacetone III, dissolved in 53 ml of methylene chloride and 17.5 ml of pyridine under stirring for 30 minutes. The temperature was maintained between -6 and -10° C. After 30 minutes, was added 50 ml of a saturated solution of Panso3when mixing and precise temperature control. After heating to room temperature, the phases were separated. The aqueous phase was extracted with methylene chloride and the organic phase was washed with 45 ml of 2 N. Hcl, bringing the pH to about 1. The organic phase is washed with Hcl 0.1 N. and then Panso3, dried over Na2SO4and evaporated to dryness to quantitatively obtain 11.5g 1,14 carbonate 14-hydroxyacetone.

11.5g 1,14 carbonate 14-hydroxyacetone was dissolved in 50 ml of DMF (DMF), was added 1.1 equivalent of chlorotriethylsilane and 3 equivalents of N-methylimidazole at room temperature. After the interaction, the mixture was poured into 500 ml of N2O and the precipitate was filtered and thoroughly washed with H2O, and then dried to obtain 12.8 g 1,14 carbonate 14β -hydroxy-7-Tes-baccatin III, however the same characteristics that shown in example 1.

Example 5: Synthesis of 13-(N-Boc-β -isobutylamino)-14β -hydroxyacetic III 1,14 carbonate

Based on 14β -hydroxy-7-s-baccatin III-1,14-carbonate, obtained as described in the above example, the method was as follows.

In a 1 l round bottom flask were placed 20 g 14β -hydroxy-7-s-1,14-carbonate-baccatin III together with 300 ml of fully dehydrated toluene; added 10 g of (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid, dissolved in CH2Cl2and 2 g of N,N-dimethylaminopyridine (DMAP), and was added 9.5 g of dicyclohexylcarbodiimide (DCC). The reaction mixture is boiled under reflux for 3 hours, then cooled to accelerate the precipitation of the product is a derivative of urea, and the mother solution was washed with a saturated solution Panso3to remove unreacted acid, then dilute hydrochloric acid to remove DMAP and, finally, again NaHCO3for neutralization. The organic phase is evaporated to dryness to obtain 41.5 g of product, which can be used directly in the next stage.

40 g of this composition was subjected to the removal of protection on two stages, first splitting s and then 2,4-dimethoxybenzaldehyde. 40 g of the composition was dissolved in 100 ml of a mixture (80:100) acetonitrile/pyridine in a nitrogen atmosphere, and the mixture was cooled to 0#x000B0; With; was added 13 ml pyridine fluoride, and left under stirring for 24 hours. The solution was poured into 2 l of water, the product was filtered and dried in vacuum. The residue was dissolved in 60 ml of methylene chloride, and this solution was added 40 ml of methanol and 0.6 N. Hcl with vigorous stirring and at 0° C. the Reaction mixture was left for 2 hours under stirring, then diluted with 150 ml of methylene chloride and shaken with a solution of NaHCO3bringing the pH to 6-7. The organic phase is evaporated to dryness, and the residue was led from acetogenin, and then dried to obtain 16.5 g 1,14-carbonate 13-(N-Boc-β -isobutylphenyl)-14β -hydroxyacetone III.

Example 6: Synthesis of 1,4-carbonate 13-(N-Boc-β -isobutylamino)-14β -hydroxyacetone-V.

Was dissolved 3 g of 1,4-carbonate 13-(N-Boc-β -isobutylamino)-14β -hydroxyacetone-III 500 ml of a mixture of dichloromethane:methanol, 9:1. Then added 10 g of basic aluminum oxide and the suspension was left under stirring overnight. Then the suspension was filtered and the solvent was evaporated to dryness. The residue was purified by chromatography on a column (hexanon 1:1) to give the 1,4-carbonate 13-(N-Boc-β -isobutylamino)-14β -hydroxyacetone-V, having the following physico-chemical and spectroscopic characteristics.

Formula: C44H57NO17

Appearance: white powder

Melting point: 245° is.

An example of a pharmaceutical composition:

Compound I (300 mg

Ethyl alcohol (digidrirovanny alcohol) 5 ml

Polysorbate 80 10 ml

DATA for BIOLOGICAL studies

1. The pharmacological activity

Analysis of cytotoxicity

The compound of formula I, paragraph 1 (Compound I) and a known reference compound paclitaxel (Taxol, one of the most active known chemotherapeutic agents) were investigated to compare their cytotoxic activity against various tumor cell lines.

Used the following cell lines carcinoma person: cell breast carcinoma MCF-7(34), drug resistant cells MCF-7 (MCF7/R), multi drug-resistant ovarian carcinoma cells A (38) and drug resistant cell line carcinoma human HCT-15.

The inhibitory activity of the test compounds on cell growth was evaluated using sulforhodamine In (SRB) (Sigma Chemical Co.) in the analysis based on the staining, which indirectly determines the number of cells by measuring the proteins associated with the membrane. Briefly, 1× 105exponentially proliferating cells were planted in 96-well microtiter plates in complete growth medium and incubated at 37° C for 15-18 hours, allowing the cells attached keychain, four button Itsa to the substrate before adding taxan. For each test taxane puts tests in parallel five 96-well microtiter plates. All cell lines were subjected to 10-12 different concentrations of each drug, including the concentration of 5-6-log range, within 72 hours at 37° C, 5% CO2. The cells were fixed in situ for 1 hour at 4° using ice 50% trichloroacetic acid. The tablets were then washed 6 times with water, and to each well was added 150 ml of 0.4% SRB. After 5 minutes incubation at room temperature the tablets were washed (rinsed) with 0.1% acetic acid and air-dried. Bound SRB was solubilizers by adding 100 μl of 10 mm Tris-base (pH of 10.5) per well and gave kept at room temperature for 5 minutes. The optical density (OD) of each well was measured at 570 nm. Under these conditions, the number of cells is proportional to OD. Determined the concentration of each drug that inhibits cell growth by 50% (IC50using empirically derived concentration of drug in the range of 10 PM - 30 mm; IC50was obtained by plotting the dependence of concentrate effect. The sustainability index RI, which is a measure of cellular resistance to a particular drug, was calculated by dividing the value of the IC50obtained for drug-resistant is among the means of cell lines on the IC 50appropriate cell lines that are sensitive to the drug (IC50MCF-7R/IC50MCF7).

Cytotoxic activity are presented in table 5.

Table 5
ProcessingIC50
MCF7MCF7/RRIAHCT-15
Paclitaxel2,19204389273
The connection I1,414104,525

Results

Due to the cytotoxicity of Compound I compared to that of paclitaxel to human tumor cells mentioned above (table 5). The results show that Compound I shows a wide range of cytotoxicity and is more potent than paclitaxel in all tested cell lines. The connection I was especially effective against drug resistant cell lines, significantly reducing RI F7 cells.

2. Pharmacokinetics

The pharmacokinetic profile of Compound I is more favorable in terms of absorption and bioavailability of as in intravenous and oral administration, than β -epimer (US 3705508), it is shown to the data presented in table 6.

Table 6
ConnectionCmax, mcg/mlDose, mg/kgTM,

minutes
T/2, hAUC,

ág/ml· h
F*, %
The connection I17,3 for 93.460,PP 60, V.V.15

5
4,7

3,3
63,41

86,4
73,4
β -epimer11,2

98,7
60, BP

60, Vladimir
30

5
4,9

3,5
45,4

90,3
50,3
*F = (U.../ U...)× 100

3. Toxicity

The toxicity study of Compound I conducted on rats according to known procedures. The results presented in table 7.

Table 7
ProcessingLD50, mg/m2VV
Paclitaxel200
The connection I180
DL50= lethal dose for 50% of tested animals.

The above data on the activity and toxicity demonstrate that Compound I is significantly more than the asset is diversified and less toxic than paclitaxel.

1. Derived taxane formula (I)

2. The method of obtaining the compounds of formula (I), in which 1,14-carbonate 13-(N-Boc-β -isobutylphenyl)-14β -hydroxy-baccatin III is treated with DBU (diazabicyclo[5,4,0]-7-undecene) in methanol or THF or alternatively, leave the solution with methylene chloride and chlorinated solvents in the presence of aliphatic alcohols selected from methanol, ethanol or propanol, and with basic alumina, for a period of time from 1 hour to 14 days.

3. The method of obtaining 1,14-carbonate-13-(N-Boc-β -ISO-utilizatorii)-14β -hydroxy-baccatin III, comprising the following stages:

a) conversion of 14β -hydroxy-10-deacetylbaccatin III triethylsilane in the 7th position derived;

b) obtaining 1,14-carbonate derivative of the product of stage (a);

C) selective acetylation of the hydroxyl in position 10;

d) the interaction of the product of stage (C) with (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboloy acid;

e) cleavage of the protective groups triethylsilyl, demetsky-benzylidene from the product from step(d).

4. The method according to claim 3, wherein silylium agent at the stage (a) is triethylchlorosilane; 1,14-carbonate-derived stage (b) receive, using phosgene in toluene in which aStore 3:1 methylene chloride/pyridine in a nitrogen atmosphere; recovery stage (C) is carried out with litigationrelated (LiHMDS) in anhydrous THF and the resulting 10-hydroxy next acetimidoyl acetylchloride; the reaction of the condensation stage (d) is carried out in an anhydrous non-polar organic solvent in the presence of a base and a condensing agent dicyclohexylcarbodiimide (DCC); triethyleneglycol-protective group on stage (e) remove pyridine fluoride in a solution of acetonitrile/pyridine in a nitrogen atmosphere, and dimethoxybenzidine-protective group is removed in methylenchloride solvent by adding methanol model HC1, and then NaHCO3.

5. The method of obtaining 1,14-carbonate 13-(N-Boc-β -isobutylphenyl)-14β -hydroxy-baccatin III, which includes the following stages:

a') selective acetylation of the hydroxyl at position-10 14β -hydroxy-10-deacetylbaccatin III;

b') receiving 1,14-carbonate derivative of the product from step (a');

with') similarobama hydroxyl in position C-7;

d') the interaction of the product from step (C) with (4S,5R)-N-BOC-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid;

e') cleavage triethylsilyl and dimethoxybenzidine protective groups of the product from step (d').

6. The method according to claim 5, wherein the selective acetylation at the stage (a') is performed in the presence with the lei scandium, ytterbium, preferably l3·7H2O, and stage (b')-(e') perform similarly to the stages (b), (a), (d) and (e) of paragraph 4.

7. The method of obtaining (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid, which comprises the following stages:

a) protection of the amino group latinola Re-group;

b) conversion of N-Boc-L-leucinol N-Boc-L-leucinol;

c) obtaining lingering derived product from step (b);

d) converting longitundinal to the corresponding carboxylic acid;

e) obtaining methyl ether carboxylic acids;

f) purification of the methyl ester (2R,3S)-3-(N-Boc)amino-2-hydroxy-5-methylhexanoic acids;

g) condensation of the product of stage (f) with 2,4-dimethoxybenzaldehyde;

h) converting the methyl ester (4S,5R)-N-Boc-2-(2,4-acid)-4-isobutyl-1-oxazolidine-5-carboxylic acid to the corresponding carboxylic acid.

8. Intermediate compound synthesis: 14-β -hydroxy-7-Tes-baccatin III or 1,14 carbonate 14-β -hydroxy-7-s-baccatin III.

9. Pharmaceutical composition having anti-cancer activity, containing the compound (I) with pharmaceutically acceptable carriers and excipients.

10. The compound (I) according to claim 1, used to obtain a drug with anti-cancer activity.



 

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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, chemical technology, medicine, biochemistry, pharmacy.

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

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: metalloorganic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing platinum complexes having the formula (Ia) or (Ib) given in the description. Method involves: 1a) the first stage wherein [PtA4]2- interacts with L under corresponding conditions in the first solvent to yield [PtA3(L)]-; 1b) the second stage wherein [PtA3(L)]- interacts with L' under corresponding conditions in the second solvent to yield cis-[PtA2(L')(L)]; 1c) in the case when Y represents halogen atom or hydroxy-group the third stage wherein cis-[PtA2(L')(L)] interacts with H2O2, Y2 or halogen containing oxidant to yield c,t,c-[PtA2Y2(L')(L)]; in the case when Y represents ester of carboxylate, carbamate or carbonate the forth stage wherein intermediate compound and wherein Y represents hydroxy-group obtained at the stage 1c) is functionalized with corresponding acylating agent; and 1d) in the case when A doesn't represent halide or differs from the parent halide the additional stage (stages) wherein at the first stage halide A of intermediate compound obtained at stage 1a), 1b), 1c) or 1d) is converted to another halide and new removing group (groups) A, such as monodentate hydroxy-, alkoxy-, carboxylate or bidentate carboxylate, phosphonocarboxylate, diphosphonate or sulfate wherein L, L' and Y have values in the description.

EFFECT: improved preparing method, expanded assortment of platinum-containing medicinal agents.

33 cl, 3 tbl, 9 dwg, 23 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to derivatives of platinum tetrachloride and to a method for their preparing also. Invention proposes compounds of the formula PtCl4 x 2 Li wherein Li represents N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotine hydroxamic acid, or isonicotine hydroxamic acid. Also, invention proposes a method for preparing these compounds that involves interaction of pyridine carboxylic acid nitroxyethylamides or hydroxamic acids, or their hydrochlorides with potassium hexachloroplatinate followed by isolation of the end product. Invention provides synthesis of the unknown early chelate platinum compounds that are physiologically active substances and can be used in medicinal practice instead cisplatin as effective anti-metastatic medicinal agents with low toxicity.

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

2 cl, 3 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, oncology.

SUBSTANCE: the method deals with polychemotherapy and is fulfilled by the following technique: it is necessary to carry out blood sampling in these patients at the quantity of 25 ml: during the 1st d of polychemotherapy one should incubate 5 ml autoblood with 50 mg/sq. m metothrexate, during the 2nd, 3d, 4th and 5th d one should incubate per 5 ml autoblood with 15 mg/sq. m bleomycin daily in thermostat at 37 C for 30 min, carry out application anesthesia and introduce chemopreparations upon autoblood into endonasal tumor component or alternate intratumor introduction of chemopreparations upon autoblood at introducing them into maxillary antrum if it is affected with tumor process. The method provides local concentration and decreased toxicity of chemopreparations due to their intratumor introduction upon autoblood.

EFFECT: higher efficiency of therapy.

1 ex, 1 tbl

FIELD: medicine, oncology, amino acids.

SUBSTANCE: invention relates, in particular, to the development of an antitumor preparation based on natural substances. Invention relates to an amino acid preparation comprising at least one modified essential amino acid obtained by treatment of amino acid by ultraviolet radiation (UV) at wavelength 250-350 nm for 12-80 h at temperature 15-30oC or with ozone at temperature 15-25oC. The modified amino acid has no toxicity for health cells. Also, invention relates to a method for preparing such preparation. Invention provides the development of an antitumor preparation based on modified amino acids and expanded assortment of antitumor preparations being without cytotoxicity for normal cells.

EFFECT: valuable medicinal antitumor properties of preparation.

8 cl, 4 tbl, 2 dwg, 4 ex

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