Semi-synthetic texan, intermediate compounds, methods of preparation and pharmaceutical composition

 

(57) Abstract:

Semi-synthetic Texan formula 1, where R1, R2- C1-8-alkyl or phenyl, R2may also represent a tert-butoxypropan; when the double bond is present in 11, 12 positions, R3is hydrogen, R4is hydroxyl or2-8-alloctype; when the double bond is absent in 11, 12 positions, methyl in position 12 has an alpha orientation, R3is a hydroxyl group or2-8-alloctype; R4is a hydrogen atom, and a pharmaceutical composition based on it has antitumor activity. 7 C. and 5 C.p. f-crystals, 2 tab.

Diterpenes with the structure taxane, in particular Taxol, known to possess anti-tumor activity against several human cancers. However, use of these drugs, especially Taxol, has some drawbacks due to unwanted side effects. For this reason, and due to the fact that these anticancer drugs quickly induce tolerance to their effects, the development of new substances, the use of which reduces the problems observed in clinical application, is of interest.

In the application WO 93/02067 (Nippon Steel) on February 4, 1993 episternal cytotoxic activity.

This invention relates to new derivatives with structures taxane received a semisynthetic method and having a strong antitumor activity. Derivatives of this invention have the structure of formula (1):

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They can be divided into two groups:

a) derivatives taxane containing olefinic double bond in position 11, 12, and hydroxyl or acetyloxy in position 10a (taxanes of formula 1a)

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(1a) (R3= H; R4= OH or alloctype)

b) derivatives taxane containing a single bond between the carbon atoms in position 11 and 12, with the methyl in position 12 alpha-oriented, and hydroxyl or alloctype in position 10 is beta (Texan formula 1b).

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(1b) (R3= OH or alloctype; R4= H)

In takanah General formula (1) R1and R2that may be the same or different, represent a C1-C8alkyl, C2-C8alkenyl, aryl (preferably phenyl) or heteroaryl group. R2may also represent a tert-butoxy group.

In the compounds of formula (1a) R3is hydrogen, a R4is hydroxyl or C2-C8alloctype.

In sedimentary formula (1) is obtained by esterification in position 13 new synthons of formula (2), using activated appropriately chain azaserine as alleluya agents, in accordance with the method described in the literature for poluentes Taxol and its analogues (see, for example, EP-A-400971, 1992, Fr. dem.86, 10400; E. Didier et al., Tetrahedron Letters 35, 2349, 1994; E. Didier et al., ibid. 35, 3063, 1994).

In the formula (2)

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where the olefinic double bond is in position 11, 12, R3represents a hydrogen atom, R4and R5is hydroxyl, C2-C8-acyloxy, alkylsilane or 2,2,2-trichlorocarbanilide-group;

when the olefinic double bond is not in the position 11, 12, methyl in position 12 is an alpha-oriented, R4is a hydrogen atom, R3and R5is a hydroxyl group, a C2-C8-acyloxy, alkylsilane or 2,2,2-trichlorocarbanilide group.

In particular, the synthons of formula (2a) are used for the synthesis of new taxan formula (1a). On the other hand, the synthons of formula (2b) are used for the synthesis of new taxan formula (1b).

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In the synthons (2a) of the olefinic double bond is in position 11, 12, and C2-C8alloctype or optionally protected hydroxyl group are in position 10. Follow the and, alkylsilane (for example, triethylsilane, O-TES) or 2,2,2-trichlorocarbanilide (O-CO-O-CH2CCl3O-TROC) group.

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In the synthons (2b) the carbon atoms in positions 11 and 12 are linked by a single bond, methylene at position 12 is an alpha-oriented, and alloctype or optionally protected hydroxyl group are in 10d-position. Therefore, in the synthons (2b), R4is a hydrogen atom, R3and R5- represent a hydroxyl group, acyloxy, alkylsilane- (such as triethylsilane, O-TES) or 2,2,2-trichlorocarbanilide (O-CO-O-CH2CCl3O-TROC) group.

After esterification in position 13 synthons (2) ezoterikovou chain protective groups are removed by conventional means, described in the literature, the result is the new taxanes of formula (1).

10-Deacetylbaccatin III (3), which can be isolated from the leaves of Taxus Baccata (G. Chauviere et coll., C. R. Acad. Sc. Ser. III, 293; 591 [1981]), is used as the only source material for obtaining synthons (2a) and (2b).

The synthons of formula (2a), which are not described in the literature, receive (Scheme 1) from compound (3) oxidation in position 10 copper acetate (II) to give the diketone (4) and the subsequent restoration of the boroughs is = OH), which is an epimer in position 10 compounds (3), contains suitable protective groups in positions 7 and 10 and used for the synthesis of taxan (1a).

New senataxin (5) is obtained as a side product of the reaction presented in Scheme 1.

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Senataxin (5) can be used for synthesis of other taxan with potential antitumor activity.

This invention relates to new derivatives with the structure senataxin received a semisynthetic method and having a strong antitumor activity. These derivatives have the structure of formula (5a)

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where R1and R2that may be the same or different, represent a C1-C20alkyl, C2-C8alkenyl, aryl (preferably phenyl) or heteroaryl. R2may also represent a tert-butoxypropan.

Taxanes of the formula (5a) is obtained by esterification of compounds of formula (5) in position 13 using as alleluya agents appropriately activated saterinone chain, as described in the literature, obtaining a semisynthetic Taxol and its analogues (see, for example, EP-A-400971; E. Didier et is about being suitable protective groups in accordance with conventional ways.

After the esterification of the compound (5) in position 13 ezoterikovou chain protective groups are removed in accordance with well-known methods described in the literature, whereby receive senataxin formula (5a).

The synthons of formula (2b), which are not described in the literature are obtained from 10-deacetylbaccatin III (3) (Scheme 2). It was found that the oxidation of the compound (3) m-chloroperbenzoic acid (MCPBA) receive a corresponding 13-ketopropane (6). After the introduction of the protective group for the hydroxyl group in position 7 triethylsilane (TESCl), the recovery of the sodium borohydride in the presence of salts of cerium (III) receive synthon (2b) (R3= OH, R4= H, R5= O-TES), which can be useful in the synthesis of taxan formula (1b). Alpha-orientation of the methyl group at position 12 in the synthons (2b) is a careful study of the spectrum of nuclear magnetic resonance.

The products of this invention were subjected to screening for their cytotoxic activity against cell lines of various tumors, when compared their activity with the activity of Taxol. In table. 1 and 2 shows the IC50Taxol and compounds of this invention: 13-[(2R,3S)-3-phenyl-2-hydroxy-3-tert-is H, R4= OH), 13-[(2R,3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino] -10-deazetil-11,12-dihydroequilin III (1b, R1= Ph, R2- tert-butoxy, R3= OH, R4= H), 13-[(2R,3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino-propanol] -C-SECO-10-deacetylbaccatin III (5a, R1= Ph, R2= tert-butoxy) and 13-[(2R,3S)-3-isobutyl-2-hydroxy-3-ciprolisina-propanol] -C-SECO-10 - deacetylbaccatin (5a, R1= isobutyl, R2= pentyl).

Compounds with different substituents in ezoterikovou chains behave similarly. The compounds exhibit unexpected advantage in comparison with Taxol against cell lines resistant to other anticancer agents such as adriamycin and CIS-platinum. Differences between Taxol and these substances even more evident in experiments in vivo, such as implantation atonicheskoy (devoid of the thymus) naked mouse tumor person. It was found that the compounds of this invention in which R2is an alkyl or Alchemilla group, unexpectedly don't show cardiotoxic activity in contrast to Taxol and its known derivatives, therefore, they can be successfully applied to patients with heart disease, which can not be used to treat so is the following pharmaceutical formulations for parenteral and oral administration. For intravenous use, mainly a mixture of polyethoxyethanol castor oil and ethanol or liposomal preparations obtained from natural phosphatidylcholine, or a mixture of natural phospholipids in the presence of cholesterol.

The following additional examples illustrate the invention.

Example 1. Receive 10 dehydro-10-deacetylbaccatin III (4).

10 g of 10-deacetylbaccatin III (3) are suspended in 350 ml of methanol where add 65 g of Cu(OAc)2. The suspension is continuously stirred at room temperature for 120 hours. Salt is filtered off and the solution chromatographic on 100 g of silica gel, elwira a mixture of hexane/ethyl acetate (6:4). After recrystallization from ligroin obtain 9.5 g (4), M+at m/z 542.

Example 2. 10-deazetil-10-epibatidine III (2a, R3= H, R4= R5= OH) and C-SECO-10-deacetylbaccatin III (5).

To a solution of 300 g (4) in 5 ml of methanol is added one equivalent of CeCl33H2O. Stirred at room temperature for 5 minutes, then add 80 ml of NaBH4. The solution is treated with a solution of NH4Cl is extracted with ethyl acetate and chromatographic on silica gel, elwira a mixture of hexane/L-10-epibatidine III has the following NMR spectrum (CDCl3): H2, d 5.68 J 6.8; H3, d 4.26 J 6.8; H5, D. 5.03 J 7.1; H7/13, m 4.76; H10, ush. with 5.20; 10 OH, ush. with 3.44; H16, 1.14; H17, 1.68; H18, 2.22; H19, 1.13; H20a, D. 4.33; H20bd 4.18; Ac, 2.31; MA, ush. 8.12 J 8, ush. t 7.60 J 8, ush. t 17.49 J 8.

Example 3. 10-deazetil-13-dehydroalanine III (6).

3 g of meta-chloroperbenzoic acid and 1 g of sodium acetate added to a suspension of 1 g of 10-deacetylbaccatin III (3) in 100 ml of CH2Cl2. The suspension is continuously stirred for 120 hours at room temperature and then diluted with 5% aqueous solution of Na2CO3. The organic phase is washed with 5% Na2CO3and evaporated to dryness. The residue is purified on silica gel, elwira a mixture of hexane/ethyl acetate (3:7). Receive 789 g of compound (6), M+at m/z 542.

Example 4. 10-deazetil-11,12-dihydro-7 - triethylenemelamine III (2b, R3= OH, R4= H, R5= O-TES).

1.6 g of compound (6) is dissolved in methylene chloride and mixed with 370 mg of 4-dimethylaminopyridine and 2.5 ml of triethylsilane. After keeping the mixture for 2 hours at room temperature it was diluted with methylene chloride and washed with water. The organic phase is evaporated to dryness. Obtain 1.72 g of residue that was mixed with 150 ml of 95% ethanol and treated with 9 g of NaBH4. Sustainahle (eluent: hexane/ethyl acetate (7:3)), receive 800 mg (2b) (R3= OH, R4= H, R5= O-TES).

C35H52O10Si, mol. weight. = 660

CI-MC (NH3): 678 (M+NH4)+(80).

IK (Kbr table): 3500, 1745, 1710, 1270, 1245, 1110, 980, 705 cm-1< / BR>
1H-NMR (400 MHz, CDCl3, room temp.): 8,15 (Bz AA'), 7,60 (Bz, C), 7,47 (Bz, BB'), 5,61 (d, J = 8,2 Hz, H-2), 5,10 (d, J = 8,3 Hz, H-5), equal to 4.97 (DD, J = 8,6, and 4.9 Hz, H-10), 4,34 (DD, J = 11,9, 8.5 Hz, H-7), the 4.29 (d, J = 8.7 Hz, H-20a), 4,27 (d, J = 8.7 Hz, H-20b), a 4.03 (ush.s, H-13), to 3.33 (d, J = 8,2 Hz, H-3), 2,48 (m, H-12), 2,24 (s, OAc), 1,71 (s, H-19), of 1.23 (d, J = 7,0 Hz, H-18), 1,11 (s, H-17), of 1.02 (s, H-16), of 0.93 (t, J = 7.9 Hz, TES), 0,54 (kV, J = 7.9 Hz, TPP).

13C NMR (50 MHz, CDCl3, room temp.): 215,1 (C), 169,9 (C), 167,7 (C), 133,4 (d), to 130.1 (d), 129,8 (C), 128,5 (d), is 83.8 (d), 80,1 (C), 79,7 (c) 77,0 (t) 73,4 (d), 71,6 (d), to 70.9 (d), 69,4 (d), 60,5 (d), of 56.4 (C) to 40.6 (d), 40,3 (C) 36,4 (t), 35,4 (t) 32,5 (kV) 32,4 (d) 25,6 (kV) 22,4 (kV) 15,6 (kV) 9,1 (kV) 5,3 (t).

Example 5. Getting 11,12-dihydro-7-TES-baccatin III (2b, R3= OH, R4= H, R5= O-TES) and 11,12-dihydroequilin III (2b, R3= OAc, R4= H, R5= OH)

500 mg 10-deazetil-11,12-dihydro-7-triethylenemelamine III (2b, R3= OH, R4= H, R5= O-TES) interact in anhydrous pyridine with 3 equivalents of acetylchloride at a temperature of 0oC for 6 hours. The reaction mixture was diluted with water and extracted with methylene chloride. ES-baccatin III, M+at m/z 702 III. The product is dissolved in methanol and treated with diluted HCl until the full desirelove. The reaction mixture is diluted with water, extracted with ethyl acetate and recrystallized from aqueous methanol. Receive 400 mg 11,12-dihydroequilin 11, M+at m/z 588.

Example 6. 13-[(2R,3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino] - 11,12-dihydroequilin III (1b, R1= Ph, R2= tert-BuO, R3= OAc, R4= H).

500 mg 11,12-dihydroequilin III (2b, R3= OAc, R4= H, R5= O-TES) was dissolved in 20 ml of toluene with 0.45 g of (4S,5R)-N-tert-butoxycarbonyl-2,2-dimetilfenil-5-oxazolidinecarboxylate acid, dicyclohexylcarbodiimide (1.03 EQ. ) and N,N-dimethylaminopyridine (0.2 EQ.) at a temperature of 80oC for 2 hours. The reaction mixture is washed with water until such time as the excess reagent is removed, and then evaporated to dryness. The residue is treated with methanol containing 1% formic acid for 4 hours at room temperature. The methanol solution was diluted with water, neutralized and extracted with ethyl acetate, the organic phase is evaporated to dryness and the residue is treated with a solution containing 1.5 EQ. di-tert-BUTYLCARBAMATE and sodium bicarbonate in 15 ml of Tetra is dry. The residue is mixed with acidified with hydrochloric acid methanol for full desirelove. The solution is then diluted with water and extracted with ethyl acetate. The residue obtained by evaporation hetero-acetic phase, chromatographic on silica gel, elwira a mixture of acetone/hexane (1: 1) to remove impurities. Obtain 580 g of the product, M+at m/z 851.

Example 7. 13-[(2R,3S)-3-benzoylamino-3-phenyl-2-hydroxypropanoyl]-11,12 - dihydroequilin III (1b, R1= R2= Ph, R3= OAc, R4= H).

500 mg 11,12-dihydro-7-TES-baccatin (2b, R3= OAc, R4= H, R5= O-TES) was dissolved in 20 ml of toluene and together with 1.5 g of (4S,5R)-N-benzoyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate acid, dicyclohexylcarbodiimide (1.03 EQ.) and N,N-dimethylaminopyridine (0.2 equiv.) the mixture was kept at a temperature of 80oC for 2 hours. The reaction mixture is washed with water until such time as the excess reagent is removed, and then evaporated to dryness. The residue is treated with methanol containing 1% formic acid for 4 hours at room temperature. The methanol solution was diluted with water, neutralized and extracted with ethyl acetate. The organic phase is evaporated to dryness and the residue is combined with methanol, podcas the atom. The residue obtained after evaporation of hetero-acetic phase, chromatographic on silica gel, elwira a mixture of acetone/hexane (1:1) to remove impurities. Obtain 530 mg of the product M+at m/z 855.

Example 8. 13-[(2R,3S)-3-phenyl-2-hydroxy-3-tert - butoxycarbonylamino-propanol] -10-EPI-10-deacetylbaccatin III (1a, R1= Ph, R2= tert-BuO, R3= H, R4= OH).

500 mg 10-deazetil-10-epibatidine III (2a, R3= H, R4= R5= OH) is dissolved in 15 ml of anhydrous pyridine and treated for 5 minutes at a temperature of 80oC three equivalents of trichlorocarbanilide (TROC-Cl) and then cooled to room temperature. To decompose the excess TROC-Cl was added 1 ml of methanol. The solution was diluted with ice water and extracted with chloroform, the organic phase is washed with diluted hydrochloric acid. The organic phase is evaporated to dryness and the residue is treated at room temperature for 24 hours with a solution of toluene containing three equivalent (4S, 5R)-N-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5 - oxazolidinecarboxylate acid, 3 equivalent dicyclohexylcarbodiimide and 0.2 equivalent of N,N-dimethylaminopyridine. The reaction mixture is washed with water and the organic phase facility within 48 hours, then diluted with water and extracted with ethyl acetate. The organic phase is evaporated in vacuum, the residue is transferred into 200 ml of a mixture of acetic acid/ethyl acetate (1: 1) and treated for 3 hours at a temperature of 30oC 11 equivalents of powdered zinc. The solid precipitate is filtered off, the solution was diluted with water, extracted with ethyl acetate and chromatographic on silica gel with a mixture of ethyl acetate/hexane (1:4). Get 512 mg of product (1a), M+at m/z 807.

Example 9. Getting a 7.9-dicritical-C-SECO-10 - deacetylbaccatin III.

To a solution of compound (5) (200 mg, 0.37 mmole) in anhydrous dimethylformamide (DMF) (5 ml) was added imidazole (75 mg, 1.11 mmole, 3 mol.EQ.) and triethylsilane (TES) (186 ml, 167.3 mg, 1.11 mmole, 3 EQ.mol), the reaction mixture was stirred at room temperature for 10 minutes. Analysis of the reaction mixture is carried out by thin-layer chromatography (hexane:ethyl acetate = 3:7, Rfinitial mass of 0.10, Rfproduct 0.80). The reaction is quenched by addition of water and CeliteR(brownmillerite), the precipitate filtered and washed with water to remove DMF, then CHCl3to remove the product. After purification column chromatography (hexane/ethyl acetate 9:1 for elution of silanol, then GE>1H64O10Si2, mol. weight = 772

CI-MC (NH3): 790 (M+NH4), (50).

IR (KBr table.): 3453, 1709, 1689, 1240, 1109, 710 cm-1.

1H-NMR (200 MHz, CDCl3, room temp.): 8,02 (Bz AA'), to 7.59 (Bz, C), 7,45 (Bz, BB'), to 5.58 (d, J = 9 Hz), H-2), 5,10 (ush.S., H-5), 4,92 (ush.m., H-13), 4,15 (ush. m , H-13), of 3.60 (2H, ush.C.), 1,98, 1,95 (s, H-18 and H-19), of 1.16 and 1.15 (s, H-16 and H-17), and 1.00 to 0.60 (m, 2 TES).

13C-NMR (CDCl3, br tempo.): 192,0, 169,2, 167,1, 143,1, 141,8, 133,6, 129,5, 128,8, 128,7, 85,8, 80,2, 75,6, 74,6, 67,6 58,4, 44,1, 42,6, 41,2. The signals of the methyl groups is very wide and represent a multiplet peaks.

Example 10. 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert - butoxycarbonylamino-C-SECO-10-deacetylbaccatin III (5a, R1= Ph, R2= tert-BuO).

To a solution of the product obtained in example 9 (126 mg, 0.16 mmole) in anhydrous toluene (5 ml) is added 67.5 mg of dicyclohexylcarbodiimide (0.327 mmole, 2 mol. equiv.) 105 mg of (4S,5R) -N-Boc-(2,4-acid)-4-phenyl-5-oxazolidinecarboxylate acid (0.327 mmole, 2 mol. EQ.) and 5 mg of 4-dimethylaminopyridine. The mixture is heated to 60oC and kept at this temperature for 24 hours, diluted with saturated aqueous NaHCO3and ethyl acetate. The residue is purified by the method of column chromatography, elwira a mixture of hexane/ethyl acetate (8:2), Paul is room temperature. The solution is alkalinized to pH 5 and evaporated to dryness under vacuum. The remainder chromatographic on a column of silica gel, elwira a mixture of methylene chloride/methanol (98:2). After recrystallization from ethyl acetate to obtain 85 mg specified in the title compound.

C43H53NO14, Mol. weight = 807

Cl-MC (NH3): 825 (M + NH4)+(20).

1H-NMR (400 MHz, CDCl3, 60oC): 8,05 (Bz AA'), 7,60 (Bz, C) of 7.48 (Bz, BB'), 7,41 (AA', o-Ph), 7,37 (BB', m-Ph), 7,29 (s, p-Ph), 6,45 (s, 9-OH), 6,23 (ddcv, J = 10,0, 7,0, 1.5 Hz, H-13), 5,64 (ush.D. JJ = 9,0 Hz, H-2), 5,49 (d, J = 9.5 Hz, NH), 5,32 (DD, J = 10,0, 3.0 Hz, H-3'), 5,26 (ush.D. J = 11.5 Hz, H-5), 5,16 (d, J = 8.0 Hz, H-20a), of 4.67 (d, 3.0 Hz, H-2'), 4,35 (ush. D. J = 9,0 Hz, H-C), the 4.29 (d, J = 8.0 Hz, H-20 ush.), 3,86 (DDD, J = 11,0, the 6.0, 6.0 Hz, H-7a), 3,70 (DDD, J = 11,0, of 6.5 and 6.5 Hz, H-7b), 2,80 (ush. DD, J = 16,0, 7,0 Hz, H-14a), 2,52 (m, H-6a), 2,44 (ush.D. J = 16,0, 10.0 Hz, H-14b), to 2.18 (s, 1-OH), 2,10 (m, H-6b), of 1.93 (s, OAc), 1,86 (ush.with. H-19), of 1.85 (d, J = 1.5 Hz, H-18), is 1.31 (s, BOC), of 1.28 (s, H-17), 1,12 (s, H-16).

Example 11. 13-[(2R,3S)-3-isobutyl-2-hydroxy-3 - caprylamidopropylamine-C-SECO-10-deacetylbaccatin III (5a, R1= Ph, R2= pentyl).

To a solution of the product obtained in example 9 (126 mg, 0.16 mmole) in anhydrous toluene (5 ml) is added 67.5 mg dicyclohexylcarbodiimide (0.327 mmole, 2 mol. equiv.) 140 mg of (4S,5R)-N-caproyl-2-(2,4-acid)-4-isobutyl-5 - oxazolidinyl at this temperature for 24 hours, then diluted with saturated aqueous NaHCO3and ethyl acetate. The residue is purified by the method of column chromatography (eluent: hexane/ethyl acetate (8: 2)), the result is 175 mg 13-ether (95%). The residue is absorbed in 50 ml of methanol/HCl (0.01%) and the reaction mixture is left at room temperature for 1 hour. The solution is alkalinized to pH 5 and evaporated to dryness in a vacuum. The remainder chromatographic on a column of silica gel, elwira a mixture of methylene chloride-methanol (98:2). After recrystallization from ethyl acetate to obtain 88 mg specified in the title compound.

Examples of farmcampsite

Example: the Solution for parenteral injection

Connection etc. 11 - 15 mg

Cremophor - 175 -"-

An absolute. alcohol - 0,4 -"-

Example B: Tablets

Connection etc. 8 50 mg

Cross-linked sodium carboxymethylcellulose - 12 -"-

Lactose (spray dried) - 134 -"-

Microcrystalline cellulose 50 mg

Silicon dioxide colloidal - 1 -"-

Magnesium stearate - 3 -"-.

1. Semi-synthetic Texan formula 1

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where R1and R2that may be the same or different, represent a C1-C8alkyl or phenyl, R2may be a m of hydrogen, R4represents a hydroxyl group or a C2-C8alloctype;

when the double bond is absent in positions 11, 12, methyl in position 12 has an alpha orientation, R3represents a hydroxyl group or a C2-C8alloctype and R4represents a hydrogen atom,

provided that when R1and R2are fenelli and regulations 11 and 12 are connected by a double bond, R4is not acetyl.

2. Connection on p. 1, representing a 13-/(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino/-10-EPI-10-deacetylbaccatin III formula 1A

< / BR>
where R1- phenyl, R2- tert-butoxy, R3- H, R4- OH.

3. Connection on p. 1, representing a 13-/(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino/-11,12-dihydroequilin III formula 1b

< / BR>
where R1- phenyl, R2- tert-butoxy, R3- acetoxygroup and R4- the hydrogen atom.

4. A method of obtaining a connection on p. 1, in which the synthons of formula 2

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where the olefinic double bond is present at position 11, 12, R3represents a hydrogen atom, R4and R5represent hydroxyl GRU is ina olefinic linkage is not in the position 11, 12, the methyl in position 12 is an alpha-oriented, R4represents a hydrogen atom, R3and R5is a hydroxyl group, a C2-C8-acyloxy, triethylsilane - or 2,2,2-trichlorocarbanilide,

subjected to esterification in accordance with known methods appropriately activated and/or protected derivative azaserine, whereby in position 13 enter acyl group

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where R1and R2take the values defined in paragraph 1,

with the subsequent removal of the protective groups by known methods.

5. The compound of formula 2

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where the double bond is present at position 11, 12,

R3represents a hydrogen atom,

R4and R5represent a hydroxyl group, a C2-C8acyloxy, triethylsilane - or 2,2,2-trichlorocarbanilide,

and when the olefinic double bond is not in the position 11, 12, methyl in position 12 is an alpha-oriented, R4represents a hydrogen atom, R3and R5represent a hydroxyl group, a C2-C8acyloxy, triethylsilane - or 2,2,2-trichlorocarbanilide,

in cachucha.

7. Semi-synthetic senataxin formula 5A

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where R1and R2that may be the same or different, represent a C1-C20alkyl or phenyl;

R2may represent a tert-butoxypropan.

8. Connection on p. 7, representing a 13-/(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino/-C-SECO-10-deacetylbaccatin III, formula 5A

< / BR>
where R1- phenyl,

R2- tert-butoxypropan.

9. Connection on p. 7, representing a 13-/(2R, 3S)-3-ISO-butyl-2-hydroxy-3-caprylamidopropylamine/-C-SECO-10-deacetylbaccatin III formula 5A, where R1- isobutyl, R2pencil.

10. The method of obtaining compounds on p. 7, where the compound of formula 5

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subjected to the conventional esterification methods, derived, appropriately activated and/or protected in ezoterikovou circuit, whereby in position 13 is introduced acyl group

< / BR>
where R1and R2take the values defined in paragraph 7,

with the subsequent removal of the protective group in the usual way.

11. Pharmaceutical composition having antitumor activity, comprising an active substance and Fara on PP.1-3 and 7-9.

12. Taxan derivative on PP.1-3 and 7-9 to obtain drugs for the treatment of cancer.

Priority points:

26.07.94 - PP.1-12;

19.06.95 - PP.1-12 varieties radicals.

 

Same patents:

, 20-epoxy-1,2, 4,7; , 1013th- hexahydroxy-11-en-9-it is complex ester group in position 13 formed (2r, 2s)-n-hexanoyl-3 - phenylisoxazol, method thereof and pharmaceutical composition" target="_blank">

The invention relates to a new taxane, namely 4,10-diacetate 2-benzoate 5, 20-epoxy-1,2, 4,7, 1013th-hexahydroxy-11-EN-9-it is complex ester group in position 13 formed (2R, 2S)-N-hexanoyl-3-phenylisoxazol having the structural formula I, which are extracted from the bark of the roots of plants of the genus Taxus extraction

The invention relates to a new method of obtaining 7-trialkylsilyl-baccatin III General formula 1

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in which the symbols R are identical or different, denote alkyl radicals with 1-4 carbon atoms, if appropriate substituted phenyl radical, from 10-desacetyl-baccatin III formula II

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In the General formula (1) each of the symbols R represents preferably a linear or branched alkyl radical with 1-4 carbon atoms

The invention relates to antiparasitics agents and, in particular, to compounds related to the avermectins and milbemycin, but containing substituents at the 3-position

The invention relates to the field of medicine and for the pharmaceutical solution of antitumor action of its receipt and perfusion solution

The invention relates to pharmaceutical industry and relates to antitumor compositions containing the derivatives taxane

, 20-epoxy-1,2, 4,7; , 1013th- hexahydroxy-11-en-9-it is complex ester group in position 13 formed (2r, 2s)-n-hexanoyl-3 - phenylisoxazol, method thereof and pharmaceutical composition" target="_blank">

The invention relates to a new taxane, namely 4,10-diacetate 2-benzoate 5, 20-epoxy-1,2, 4,7, 1013th-hexahydroxy-11-EN-9-it is complex ester group in position 13 formed (2R, 2S)-N-hexanoyl-3-phenylisoxazol having the structural formula I, which are extracted from the bark of the roots of plants of the genus Taxus extraction

The invention relates to the field of macrolides
The invention relates to a method of purification of 10-deacetylbaccatin III and Taxotere

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

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