8-foratricilegnousata or their pharmaceutically acceptable salts accession acids, the method of production thereof, pharmaceutical composition, the intermediate and the method of production thereof

 

(57) Abstract:

The inventive new 8-ftoroproizvodnykh anthracyclinebased General formula I:

,

where R is H, OH; R1Is H, OH, MeO; NH2shows that aminosalicylic may be in the axial or Equatorial configuration, or their pharmaceutically acceptable salts accession acids. Compounds prepared by condensation of the corresponding 8-forestration with the compound of the formula IIIa or IIIe

,

where X is chlorine or n-nitrobenzyloxy; R2-triptoreline or allyloxycarbonyl group, followed by removal of protective groups and, if necessary, transform the radical R is hydrogen, R is a hydroxy-group through the corresponding 14-bromo derivatives; intermediate compounds IIIa and IIIe and the retrieval method, which consists in the interaction of methyl-2,3,6-trideoxy- -L-glyceroglycolipids-4-wlosy with hydroxylamine, followed by recovery of the resulting mixture of SYN - and antioxidan, protection of the resulting amino group and sharing their epimeres, with subsequent transformation of the latter into the corresponding 1-hydroxy and target product. The intermediate polevye properties. 9 C. and 7 C.p. f-crystals, 4 PL.

The invention relates to a glycosidic derivative 8-forestration formula I:

< / BR>
where: R is H, OH, OR OR;

R1H, OH, OCH3;

R" CHO-COCH3or acyl residue derived from a carboxylic acid containing up to 6 carbon atoms; and

NH2shows that amine Deputy may be in axial configuration (natural configuration) or Equatorial configuration (EPI - configuration);

and to their pharmaceutical acceptable salts.

Daunorubicin (daunomycin), 4-demethoxygeldanamycin (idarubicin) and their derivatives containing gidrauxilirovaniu side chain (doxorubicin), are glycosides with known antitumor properties, obtaining and the use of which has already been described. (F. Arcamone "Doxorubicin Anticancer Antibiotics". Medicinal Chemistry Series, Vol.17. Academie Press, 1981).

Currently surprisingly been found that the replacement of the H atom by atom F in position C-8 non-glycosidic part of the molecule increases the activity and selectivity of these compounds, which thus suddenly have a higher ability (strength) in comparison with the known anthracyclines, especially in the case of tumor cells, ustice-forestration formula (I):

< / BR>
where: R is H, OH, OR OR;

R1H, OH, OCH3;

R" CHO-COCH3or acyl residue derived from a carboxylic acid containing up to 6 carbon atoms; and

NH2shows that amine Deputy may be in axial configuration (natural configuration) or Equatorial configuration (EPI configuration);

and their pharmaceutically acceptable salts.

One of the preferred salts of the present invention is the hydrochloride compounds of formula (I).

More specifically, the present invention relates to the following compounds:

4 dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-aminocoumarin (R R1H);

4 dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocoumarin (R R1H);

8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocoumarin (R H, R1OCH3);

8-fluoro-3'-deamino-4'-deoxy-4'-aminocoumarin (R H, R1OCH3);

8-fluoro-3'-deamino-4'-deoxy-4'-aminoterminal (R H, R1OH);

8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminoterminal (R H, R1OH);

4 dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-aminocoumarin (R OH, R1H) and its esters in position C-14;

8-fluoro-3'-deamino-4'-deoxy-4'-aminodeoxy (R H, R1OCH3) and its esters in position C-14.

The compounds of formula (I) and their pharmaceutically acceptable salts are obtained by condensation of 8-forestration formula (II):

< / BR>
where R1is the same as defined above, with a compound of formula IIIa or IIIe:

< / BR>
in which X is a leaving group that can form under conditions of condensation stable carbocation that can join a hydroxyl group in position C-7, and R2is a protected amino group, to obtain a glycoside of the formula (IV)

< / BR>
in which R1and R2are as defined above, and () indicates that the substituent R2may be in the axial or Equatorial configuration.

When removing the amino-saltney group of the compounds of formula IV is obtained 8-forestrycellulose formula I in which R and R1are as defined above.

Anthracyclinebased formula I may turn into one of its pharmaceutically acceptable salts, or a compound of formula I or its pharmaceutically acceptable salt can broniruutsja and received a 14-bromo-derivative can be hydrolyzed to obtain enthrallingly of its pharmaceutically acceptable salts.

According to the invention, the preferred leaving group X of the compounds of the formula III is halogen, such as bromine or chlorine, preferably chlorine, or a pair-nitrobenzyloxy group. Amino-Saldana group R2is preferably triptorelin or allyloxycarbonyl.

The reaction conditions for the condensation reaction between the compound of formula II and a compound of formula IIIa or IIIe, to obtain the compound of formula IV may also vary according to the type of substitution of the compounds of the formula IIIa or IIIe.

The reaction glycosidase is carried out in an inert organic solvent in the presence of a condensing reagent.

Hydrocarbon solvents such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated solvent such as chloroform, methylene chloride or dichloroethane, and mixtures thereof can be used. Methylene chloride is the preferred solvent.

Condensing agents may be salts such as triftorbyenzola silver perchlorate, silver, a mixture of oxide of mercury (2) and bromide of mercury, triftorbyenzola of trimethylsilyl; a Lewis acid such as the halide is the temperature value of the reaction can vary from -40oC to 40oC, preferably from -20oC to 20oC, and the reaction can last from 15 minutes to 3 o'clock

Dehydrating agent, such as activated molecular sieves, preferably present in the reaction mixture.

During the reaction or at the end of it to the reaction mixture may be added an organic base, such as pyridine, kallidin, N,N-dimethylaminopyridine, triethylamine or the acceptor of the proton.

According to the invention, the conditions for removal of the amino-protective group of the compounds of formula IV in which R1and R2are as defined above, to obtain the compound of formula I in which R is H and R1is the same as defined above, can vary in accordance with the mechanism of substitution of compounds of formula IV.

When the amino-protective group is triptoreline, the deprotonation reaction is carried out in a polar solvent such as water, methanol, ethanol, pyridine, dimethylformamide or mixtures thereof, in the presence of stoichiometric or greater than stoichiometric amount of an inorganic base, such as NaOH, KOH, LiOH, Ba(OH)2or their carbonates. The reaction temperature may vary from 0oC is licarbazepine, the deprotonation reaction is carried out in an inert solvent in the presence of a metal complex, such as (tetranitroaniline)-palladium, as described, for example, in Tetrahedron Letters, 30, 3773 (1089), or (tetracarbonyl)-Nickel, as described, for example, in J. Org. Chem. 38, 3233 (1973).

If necessary, the compound of formula I in which R is hydrogen and R1is the same as defined above, can be transformed, respectively, in the compound of formula I in which R is OH, and R1is the same as defined above, by synthesized in position C-14, followed by hydrolysis of 14-bromo-derivative, obtained by this method. Bromination and subsequent hydrolysis are described in U.S. Pat. USA N 4 122 076. Bromination of compounds of formula I in which R is H and R1is the same as defined above, is carried out with bromine in chloroform to obtain 14-bromo-derivative, which after hydrolysis at ambient temperature for 48 h using an aqueous solution of sodium formate is obtained the compound of the formula I in the form of a free base, in which R is OH, and R1is the same as defined above, and which by treatment with hydrochloric acid in the us General formula II and the way they are received.

This method is illustrated by reaction scheme (A).

The first stage of the method involves the oxidation of apocopate General formula V in which R1is the same as defined above, to obtain epoxyketone General formula VI, in which R1is the same as defined above. Epoxied V can be obtained as described in U.S. Pat. England N 2 125 030.

Scheme A(see Annex).

The oxidation reaction may be conducted according to methods generally known to experts in the field of technology. Methods involving the use of dimethyl sulfoxide, such as oxidation method Moffat and the like, or using pyridine-chromium complexes, such as chloramine pyridinium, are preferred.

The second stage of the method presented in scheme A, involves the reaction of epoxyketone VI with generator nucleophilic fluoride, to obtain 8-fluorinated compound of the formula VII, in which R1is the same as defined above.

Generator nucleophilic fluorine may be, for example, a complex of pyridine with hydrofluoric acid, and the preferred method to implement this stage is stirring the solution or suspension coeliadinae of foroperation formula VII to the compound of formula II. This can be accomplished by known methods such as bromination and solvolysis, if necessary, protecting the keto group [Can. J. Chem. 49, 2712 (1973); J. Amer. Chem. Soc. 98, 1969 (1976); J. Amer. Chem. Soc. 98, 1967 (1976)]

The invention relates also to the amino sugars of the formula III in which X and R2are as defined above, and to the way they are received, including:

a) reaction of methyl 2,3,6-trideoxy-alpha-L-glycero-exacerbated-4-wlosy formula VIII:

< / BR>
with hydroxylamine or salt on his accession acid to form a mixture of SYN and anti Asimov formula IX:

< / BR>
b) recovering the above-mentioned mixture, then protection of the resulting amino group with trifluoracetyl group and the separation of the thus obtained 4-N-trifurcation of epimeres formula Xa and Xe:

< / BR>
or, if preferred, protection of the resulting amino group with allyloxycarbonyl group, and division 4-N-allyloxy-carbonyliron of epimeres formula XIa and XIe:

< / BR>
C) if it is preferred, as an alternative to the above-mentioned stages of the reaction of methyl-2,3,6-trideoxy- -L - glycero-exacerbated-4-wlosy formula VIII with a reducing agent in the presence of ammonium salts, the protection thus formed is through groups, and separation of epimeres formula Xa and Xe or XIa and XIe;

(d) making each epimer Xa and Xe in the corresponding 1-hydroxy-derivative of formula XIIa and XIIe:

< / BR>
or, if preferred, the transformation of each of ephemera XIa and XIe in the corresponding 1-hydroxy-derivative of formula XIIIa and XIIIe:

< / BR>
d) the transformation of listed 1-hydroxy-derivatives XIIa and XIIe or XIIIa and XIIIe into the corresponding compounds of formula IIIa and IIIe, in which X is chlorine, and R2is the same as defined above, or, if this is desirable, the transformation of each of the specified 1-hydroxy-derived XIIa and XIIe or XIIIa and XIIIe into the corresponding compounds of formula IIIa and IIIe, in which X is a pair-nitrobenzyloxy group, and R2is the same as defined above.

In stage a) methyl-2,3,6-trideoxy- -L - glycero-exacerbated-4-ulose VIII may be treated with hydrochloric acid hydroxylamine in triethylamine to obtain the SYN and anti oximes IX.

In stage b) the oxime IX can be restored borane in tetrahydrofuran or bis-dimethoxyethoxy sodium-aluminum-hydride (Metricom) in tetrahydrofuran, toluene or dioxane. The reaction temperature may be in the range between -20oC and 20oC, and the duration d is s in carbon tetrachloride or diethyl ether at ambient temperature, preferably in the presence of an organic base such as triethylamine or pyridine, to obtain a mixture of N-trifurcation derivatives, of which separately by chromatographic separation obtained the relevant substances of the formula Xa and Xe. If it is preferred, restored the mixture can be subjected to reaction with allylchloroformate in tetrahydrofuran in the presence of organic bases such as pyridine, triethylamine and the like, at temperatures between -20oC and 20oC for 3-12 h, to obtain a mixture of N-allyloxycarbonyl, of which the corresponding compounds of formula XIa and XIe obtained by chromatographic separation.

Alternatively, in stage C) the restoration of wlosy formula VIII can be carried out using cyanoborohydride sodium and ammonium acetate or ammonium chloride in tetrahydrofuran, diethyl ether, methanol or ethanol at a temperature between -20oC and 20 oC. the Recovered mixture can be processed as described in stage b).

In stage (d) making each epimer Xa and Xe into the corresponding 1-hydroxy-derivatives XIIa and XIIe or, if preferred, the transformation of each of ephemera XIa and XIe in soo Heating may be to a temperature of between -70oC and 100oC for a time between 30 min and 3 h, using an aqueous solution of acetic acid, triperoxonane or hydrochloric acid. The concentration of the aqueous acid solution may be between 5 and 30

In stage d) each 1-hydroxy-epimer of formula XIIa, XIIe, XIIIa and XIIIe may be first processed over night at 0oC anhydride triperoxonane acid and then dissolved in diethyl ether and subjected to reaction overnight gaseous hydrogen chloride, to obtain each individual epimer of formula IIIa and IIIe, in which X is chlorine, and R2is the same as defined above.

If preferred, each of these 1-hydroxy-epimer of formula XIIa, XIIe, XIIIa and XIIIe can be dissolved in pyridine or dimethylformamide or dimethylsulfoxide in the presence of organic bases and processed pair-nitrobenzofurazan at a temperature between -20 oC and 20oC for 1-6 hours to get each individual epimer of formula IIIa and IIIe, in which X is a pair-nitrobenzyloxy group, and R2is the same as defined above.

The invention relates also to pharmaceutical compositions containing as an active start anthracyclin diluent.

A therapeutically effective amount of a compound of the invention is mixed with an inert carrier. Can be used conventional media, and the composition may be prepared in the usual way.

Compounds of the invention are effective in therapeutic treatment of humans or animals. In particular, the compounds of the invention are useful as anticancer agents by assigning therapeutically effective amounts of compounds cure the patient.

Example 1. 9-Acetyl-9,8-(8H)-epoxy-7,10-dihydro-6,11-dihydroxy-5,12 - naphtalen-dione (VI, R1H). 9-(1'-hydroxyethyl)-9,8-(8H)-epoxy-7,10-dihydro-6,11 - dihydroxy-5,12-naphtalen-dione (VI, R1H), obtained as described in U.S. Pat. England N 2 125 030 (1.9 g, 5.6 mmol) and dissolved in methylene chloride (150 ml), added at ambient temperature and stirring to a suspension Harrogate pyridinium (1.8 g, 8.5 mmol). The reaction mixture was stirred over night, diluted by addition of methylene chloride and washed with water (2 100 ml). The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum to obtain the residue, which crystallized from ethyl acetate. Obtain 1.78 g (yield 90) connection with tempera who 3H); 3,01 (double doublet, J 20 Hz, 1H), 3,4 4,2 (multiplet, 4H); 7,80 (multiplet, 2H), 8,30 (multiplet, 2H); 13,39 (singlet, 1H); 13,42 (singlet, 1H).

This way, you receive the following connections:

4-methoxy-9-acetyl-9,8-(8H)-epoxy-7,10-dihydro-6,11-dihydroxy - 5,12 - naphtalen-dione (VI, R1OCH3and

9-acetyl-9,8-(8H)-epoxy-7,10-dihydro-4,6,11-trihydroxy-5,12 - naphtalen-dione (VI, R1OH).

Example 2. 9-Acetyl-8-(8H)-fluoro-7,10-dihydro-6,9,11-trihydroxy-5,12 - naphtalen-dione (VII, R1H). A mixture of 9-acetyl-9,8-(8H)-epoxy-7,10-dihydro-6,11-dihydroxy-5,12 - naphtalen-dione (0.6 g, 1.7 mmol), obtained as in example 1, and complex hydrofluoric acid/pyridine (70-cent solution, 21 ml) is stirred for 24 h in a current of nitrogen at ambient temperature. The reaction mixture is then poured on ice and water and stirred for 30 minutes the precipitate is filtered, washed with water until until neutral and dried at 40oC under vacuum. After crystallization get 0,380 g (yield 60) compounds with a melting point 248-252oC.

NMR (CDCl3d ): 2,50 (doublet, 3H, Jnfthe 2.6 Hz); of 3.0-3.4 (multiplet, 4H); 4.25 in (singlet, 1H); 4,78 (three doublet, 1H, Jnf48,4 Hz); 7,80 (multiplet, 2H); 8,30 (multiplet, 2H), 13,0 (singlet, 1H); 13,op-7,10-dihydro-6,9,11-trihydroxy - 5,12-naphtalen-dione (VII, R1OCH3and

9-acetyl-8(8H)-fluoro-7,10-dihydro-4,6,9,11-tetrahydroxy-5,12 - naphtalen-dione (VII, R1OH).

Example 3. 9-Acetyl-8(8H)-fluoro-10-hydro-6,7(7H),9,11 tetrahydroxy-5,12 - naphtalen-dione (II, R1H). A mixture of 9-acetyl-8(8H)-fluoro-7,10-dihydro-6,9,11-trihydroxy-5,12 - naphtalen-dione (0.1 g, 0.26 per mmol), obtained as in example 2, and bromine (0.4 mmol) in carbon tetrachloride (30 ml) is irradiated for one hour, 500-watt sun lamp (quartz). The reaction mixture was washed with saturated aqueous sodium bicarbonate and then with water, dried over sodium sulfate, filtered and evaporated under vacuum to obtain the residue, which was purified on a flash chromatography. Get 0,028 g (exit 30) of the reaction product.

NMR (CDCl3d ): 2,54 (doublet, 3H, Jnfthe 2.2 Hz); 3,18 (two doublet, 1H, J 18 Hz); 3,30 (two doublet, 1H, J 18 Hz); 3,65 (doublet, 1H, Jnf3 Hz); 4,60 (broadened singlet, 1H); 4,98 (two doublet, 1H, Jnf46,2 Hz); 5,18 (broadened doublet, 1H, Jnf13 Hz); 7,80-of 7.90 (multiplet, 2H); 8,20-8,43 (multiplet, 2H); to 13.29 (singlet, 1H); 13,53 (singlet, 1H).

Following this way, you receive the following connections:

4-methoxy-9-acetyl-8(8H)-fluoro-10-hydro-6,7(7H), 9,11 - tetrahydroxy-5,12-naphtalen-dione (II, R1OCH3and

9-acetyl-8(8H)-fluoro-riverceramic - a-L-threo-hexosaminidase (Xa) and methyl-2,3,4,6-tetradeoxy-4 - triptoreline - a-L-Erythro-hexosaminidase (Xe). A mixture of 2.5 g of methyl 2,3,6-trideoxy - a-L - glyceroglycolipids-4-wlosy (VIII), 2.4 g of hydrochloric acid hydroxylamine and 3.33 ml of methanol is boiled with reverse drains phlegmy within 2 hours the Solvent is evaporated under vacuum and the resulting oily residue is mixed with 150 ml of water and extracted with 200 ml methylene chloride (three times). The extracts are dried over sodium sulfate, filtered and evaporated under vacuum to obtain the residue, which was purified flash chromatography, elwira 6/4 mixture of hexane and diethyl ether. Get 2,42 SYN/anti mixture Asimov (IX) in a viscous liquid form. This viscous liquid (0,830, 5.21 mmol) dissolved in toluene (15 ml) and to this solution in a stream of nitrogen is added dropwise at -40oC bis-methoxyethoxy-sodium-aluminum-hydride (24.5 mmol). The reaction mixture was stirred at -40oC for 1/2 h at ambient temperature for 4 h, after which water is added (0.5 ml), an aqueous solution of sodium hydroxide (0.5 ml) and water (1.5 ml). The two phases are separated, the organic phase is dried over sodium sulfite, filtered through celite and evaporated under vacuum to obtain crude compound which is suspended in carbon tetrachloride. Dropwise added triethylamine (of 2.27 ml, 16.3 m is ywaniem. After 3 hours and further stirring at 0oC, the reaction mixture was diluted with methylene chloride and washed with water, 10% aqueous solution of sodium bisulfate and 8 th aqueous solution of sodium bicarbonate. The organic phase is dried over sodium sulfate, filtered and evaporated on a vacuum to get the crude reaction product, which was purified on a flash chromatography. Elution with a mixture 15/1 methylene chloride/diethyl ether gives compound Xa (to 0.480 g, yield 38).

NMR (CDCl3d ): 1,10 (doublet, 3H, J 8 Hz); 1.5 to 2.0 (multiplet, 4H); 3,31 (singlet, 3H); 3,8-4,3 (multiplet, 2H); 4,6-4,8 (multiplet, 1H); at 6.8 (singlet, 1H).

Elution 10/1 mixture of methylene chloride/diethyl ether gives compound Xe (to 0.480 g, yield 38).

NMR (CDCl3d ): 1,15 (doublet, 3H, J 8 Hz); 1.7 to 1.9 (multiplet, 4H); 3,32 (singlet, 3H); 3.6 to 3.8 (multiplet, 2H); 4,6-4,7 (multiplet, 1H); at 6.8 (singlet, 1H).

Example 5. Methyl-2,3,4,6-tetradeoxy-4-triptoreline - a-L-threo-hexosaminidase (Xa) and methyl-2,3,4,6-tetradeoxy-4 - triptoreline - a-L-Erythro-hexosaminidase (Xe). A mixture of methyl-2,3,6-trideoxy - a-L-threo-exacerbated-4 - wlosy (VIII) (2 g, 13.8 mmol), ammonium acetate (10.7 g, 139 mmol) and cyanoborohydride sodium (2,84 g, 45 mmol) in methanol (480 ml) is stirred p ml). After 10 min of additional stirring the resulting solution was washed with chloroform (400 ml). The aqueous phase is separated, adjusted to pH 8 by adding sodium bicarbonate and extracted 7 times with 300 ml of chloroform. The extracts are dried over sodium sulfite, filtered and evaporated under vacuum to obtain the crude reaction product, which after processing anhydride triperoxonane acid (5.8 ml), as described in example 4 gives the opportunity to get two connections Xa (0.28 g) and Xe (1.5 g).

Example 6. Methyl-2,3,4,6-tetradeoxy-4-allyloxycarbonyl - a-L-threo - hexosaminidase (XIa) and methyl-2,3,4,6-tetradeoxy-4 - allyloxycarbonyl - a-L-Erythro-hexosaminidase (XIe). The recovered mixture of 0.58 g, 4 mmole), obtained as described in example 4 and dissolved in tetrahydrofuran (6 ml), treated at 0oC pyridine (0,55 ml) and allylchloroformate (0,82 g, 6.8 mmol) dissolved in tetrahydrofuran (2 ml), in the specified order. The reaction mixture was stirred for 6 h at ambient temperature, after which water is added and the mixture extracted with methylene chloride (5 times, each time with 10 ml). The extracts are dried over sodium sulfate, filtered and evaporated under vacuum to obtain the residue, which eyes is use compound XIa (0,366 g, exit 40).

NMR (200 MHz, CDCl3d ): 1,08 (doublet, J 65 Hz, 3H); 1.2 to 2.1 (multiplet, 4H, ); 3,31 (singlet, 3H); 3,4-3.5 (multiplet, 1H); 3,63 (doublet, 1H, J of 10.73); was 4.02 (triplet, doublet, 1H, Jn6,5 Hz, Jn1,6 Hz); 4,54 (doublet, 2H, J 5.6 Hz); 5,18 (two doublet, 1H); 5,27 (two doublet, 1H); 5,9 (multiplet, 1H).

Connection XIe (0,395 g exit 43).

NMR (200 MHz, CDCl3d ): 1,08 (doublet, J 6.5 Hz, 3H); 1,4-1,9 (multiplet, 4H); 3,31 (singlet, 3H); 3,4-3.5 (multiplet, 1H); 3,52 (Quartet, doublet, 1H, J H-Me and 6.5 Hz, JH-H9.9 Hz); 4,46 (doublet, 1H, J of 10.7 Hz); 4,54 (doublet, 2H, J 5.6 Hz); 4,63 (doublet, 1H, J < 1 Hz); 5,18 (two doublet, 1H); 5,27 (two doublet, 1H); 5,9 (multiplet, 1H).

Example 7. 2,3,4,6-tetradeoxy-4-triptoreline - a-L-Erythro - hexose-pianotype-nitrobenzoate (IIIe, R2NHCOCF3X pair of NO2WITH6H4COO). A mixture of 150 mg of methyl-2,3,4,6-tetradeoxy-4-Cryptor-acetamido - L - Erythro-exacerbated (Xe), obtained as described in example 5, and 20 aqueous solution of acetic acid (15 ml) is heated to 80oC for 3 hours, the Reaction mixture is evaporated under vacuum to obtain 2,3,4,6-tetradeoxy-4-triptoreline - L-Erythro-hexosaminidase (XIIe) in the form of white solid, which was dissolved in 2.5 ml of pyridine and treated at 0oC with 177 mg para-neither the feature is extracted with chloroform (5 times, each time with 3 ml). The extracts are washed with 3 N sulfuric acid, water, and 8% sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum to obtain compound IIIe (200 mg, yield 85) in the form of a viscous yellow liquid.

NMR (60 MHz, CDCl3d ): 1,25 (doublet, J 6 Hz, 3H); 1,9-2,2 (multiplet, 4H, ); 3,6-4,0 (multiplet, 2H); 6,0 (singlet, 1H); 6,35 (multiplet, 1H); 8,2 (singlet, 4H).

Example 8. 2,3,4,6-tetradeoxy-4-triptoreline - a L-threo-hexoxyethanol-para-nitrobenzoate (IIIa, R2NHCOCF3X pair of NO2-C6H4-COO). On the basis of methyl-2,3,4,6-tetradeoxy-4-triptoreline - a-L treeexpanded (Xa), obtained as described in example 4, get the connection specified by the procedure described in example 7. TCX on the plates Kieselgel (Merck F254) using the solvent system: hexane/ethyl acetate (3:1) gives Rf0,43.

Example 9. 2,3,4,6-tetradeoxy-4-allyloxycarbonyl - a-L-threo-hexoxyethanol-para-nitrobenzoate (IIIa, R2NHCOOCH2CH=CH2X pair of NO2-C6H4-COO). A mixture of 200 mg of methyl-2,3,4,6-tetradeoxy-4-allyloxycarbonyl - a - L-threo-exacerbated (XIa), obtained as described in example 6, and 20 ml of 20-but what cosmology vacuum to obtain 2,3,4,6-tetradeoxy-4 - allyloxy-carboxamido - a-L-threo-hexosaminidase (XIIIa) in the form of a viscous liquid, which was dissolved in 4 ml of pyridine and treated with 120 mg para-nitrobenzotrifluoride. The reaction mixture was stirred for 2 h at 0oC, water is added and the mixture extracted with chloroform (5 times, each time with 4 ml). The extracts are washed with 3 N sulfuric acid, water, and 8% sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum to obtain compound IIIa (260 mg, yield 81). TCX on the plates Kieselgel (Merck F254) using the solvent system: methylene chloride/acetone (95:5) gives Rf0,40.

Example 10. 2,3,4,6-tetradeoxy-4-allyloxycarbonyl - a - L-Erythro-hexoxyethanol-para-nitrobenzoate (IIIe, R2NHCOOCH2CH=CH2X-pair - NO2-C6H4-COO). On the basis of methyl-2,3,4,6-tetradeoxy-4-allyloxy-carboxamid - a-L-Erythro-exacerbated (XIe), obtained as described in example 6, get the connection specified by the procedure described in example 9. TCX on the plates Kieselgel (Merck F254) using the solvent system: hexane/ethyl acetate (95:5) gives Rf0,31.

Example 11. 2,3,4,6-tetr,6-tetradeoxy-4-triptoreline - a-L-Erythro-hexose-pyranosyl-para-nitrobenzoate (IIIe, R2NHCOCF3X-pair-NO2-C6H4-COO), obtained in accordance with example 7 in 5 ml of anhydrous methylene chloride is saturated at 0oC anhydrous hydrogen chloride. After standing overnight at 0oC precipitated p-nitrobenzoic acid is filtered off and the solution is evaporated under vacuum to obtain compound which is used for the reaction combinations without additional purification.

Example 12. 2,3,4,6-tetradeoxy-4-triptoreline-alpha-L - threo-hexose-pernaselli (IIIa, R2NHCOOF3X Cl). On the basis of 2,3,4,6-tetradeoxy-4-triptoreline - L-threo-hexoxyethanol-para-nitrobenzoate (IIIa, R2NHCOCF3X-pair-NO2-C6H4-COO), obtained as described in example 8, to receive the specified connection, following the procedure described in example 11.

Example 13. 2,3,4,6-tetradeoxy-4-allyloxycarbonyl-L-tert-hexose-pernaselli (IIIa, R2NHCOOCH2CH= CH2X Cl). A solution of 270 mg of 2,3,4,6-tetradeoxy-4-allyloxycarbonyl-L-threo-hexoxyethanol-para-nitrobenzoate (IIIa, R2NHCOOCH2-CH=CH2X-pair-NO2-C6H4-COO), obtained in accordance with example 9, in 6 ml of anhydrous methylene chloride is nitrobenzoyl acid is filtered off and the solution is evaporated under vacuum, to obtain a connection, which is used for the reaction combinations without additional purification.

Example 14. 2,3,4,6-tetradeoxy-4-allyloxycarbonyl-L-Erythro - hexosaminidase (IIIe, R2NHCOOCH2CH=CH2X Cl). On the basis of 2,3,4,6-tetradeoxy-4-allyloxycarbonyl-L-retroexpress-paranitrobenzoic (IIIe, R2NHCOOCH2-CH=CH2X-pair-NO2-C6H4-COO), obtained in accordance with example 10, receive the specified connection, following the procedure described in example 13.

Example 15. 4 dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-amino-daunorubicin hydrochloride (I, R H, R1H). A mixture of 120 mg of 9-acetyl-8(8H)-fluoro-10-hydro-6,7(7H), 9,11-tetrahydroxy-5,12-naphthacenedione (II, R1H), obtained as described in example 3, 240 mg 2,3,4,6-tetradeoxy-4-triptoreline-a-1-Erythro-hexopyranosyl-para-nitrobenzoate (IIIe, R2NHCOCF3X NO2-C6H4-COO), obtained as described in example 7, in 60 ml of dry methylene chloride and 20 ml of diethyl ether and in the presence of molecular sieves (4 Angstrom) at 0oC is treated with 0,225 ml triftoratsetata of trimethylsilyl. The reaction mixture was stirred for 15 min at 0oC and quenched with pomoshchi white precipitate, and the filtrate is evaporated under vacuum to obtain the residue, which was purified on a flash chromatography. Elution with a mixture of methylene chloride/acetone (95:5) gives 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-triftoratsetilatsetonom (IV, R1H, R2NHCOCF3) (108 mg, yield 60).

H-NMR (200 MHz, CDCl3d ): 1,15 (doublet, J 8 Hz, 3H); 1.7 to 1.9 (multiplet, 4H); 2,45 (singlet, 3H); 3,19 (doublet, J 19 Hz, 1H); 3.33 and (two doublet, JH-F3,6, J 19 Hz, 1H); 3.6 to 3.8 (multiplet, 2H); 3,98 (singlet, 1H); 4,91 (two doublet, JH-F50 Hz, 1H); 5.17 to (two doublet, JH-F12 Hz, 1H); 5,26 (multiplet, 1H); 6,21 (broadened doublet, 1H); 7,86 (multiplet, 2H); and 8.4 (multiplet, 2H); 13,35 (singlet, 1H); made 13.36 (singlet, 1H). A suspension of 78 mg of N-trifluoracetyl derived in 15.6 ml of 0.2 M solution of barium hydroxide is stirred for 2 h in a stream of nitrogen at room temperature. The reaction mixture is neutralized with carbon dioxide, and then extracted with chloroform, the combined extracts dried over anhydrous sodium sulfate and concentrated to small volume. Hydrogen chloride and diethyl ether are added to obtain the above compound (I, R H, R1H) (56 mg, yield 80). TCX on the plates Kieselgel (Merck F254) using the solvent system: chloroform/ methanol">

Hydrochloride 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-amino-daunorubicin (I, R H, R1H).

TCX on the plates Kieselgel (Merck F254) using the solvent system: chloroform/methanol/water (65:30:10), gives Rf0,47.

H-NMR appropriate trifurcated-derived says:

H-NMR (200 MHz, CDCl3, among other things d ): 3,17 (doublet, J 19 Hz, 1H, H -10 ACU); 3,31 (two doublet, JH-F3,6, J 19 Hz, 1H, H -10 EQ); 3,8-4,3 (multiplet, 2H, H-4', H-5'); 4,89 (two doublet, JH-F50 Hz, 1H, H-8); 5.25-inch (two doublet, JH-F12 Hz, 1H, H-7); 5,46 (multiplet, 1H, H-1').

Hydrochloride 8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R H, R1OCH3). TCX on the plates Kieselgel (Merck F254) using the solvent system chloroform/methanol/water (60:30:10), gives Rf0,41.

H-NMR appropriate trifurcated-derived says: H-NMR (200 MHz, CDCl3, among other things d ): 3,17 (doublet, J 19 Hz, H-10 ax); 3,5 (two doublet, JH-F3.6 Hz, J 19 Hz, 1H, H-10 EQ); 4,10 (singlet, 3H, OCH3).

Hydrochloride 8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R H, R1OCH3). TCX on the plates Kieselgel (Merck F254) using the solvent system chloroform/methanol/water (60:30:10), gives Rf0 other (d ): 3.15 in (doublet, J 19 Hz, 1H, H-10 ax); 3,49 (two doublet, JH-F3.6 Hz, J 19 Hz, 1H, H-10 EQ); 4,08 (singlet, 3H, OCH3).

Example 16. Hydrochloride 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-aminoadenosine (I, R H, R1H). A mixture of 200 mg of 9-acetyl-8(8H)-fluoro-10-hydro-6,7(7H), 9,11-tetrahydroxy-5,12-naphthacenedione (II, R1H), obtained as described in example 3, 157 mg 2,3,4,6-tetradeoxy-4 - allyloxycarbonyl-L-threo - hexopyranoside (IIIa, R NHCOOCH2CH=CH2X Cl), obtained as described in example 13, in 60 ml of dry methylene chloride and in the presence of molecular sieves (4 at 0oC is treated with a solution of 134 mg triftoratsetata silver in 10 ml of diethyl ether. After 45 min the mixture is filtered to remove the resulting white precipitate, and the filtered solution is treated with saturated aqueous sodium bicarbonate. The organic layer is separated and evaporated under vacuum to obtain the residue, which was purified on a flash chromatography. Elution with a mixture of methylene chloride-acetone (95: 5) gives 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-allyloxycarbonyl (IV, R1H, R2NHCOOCH2CH=CH2) (160 mg, yield 53).

H-NMR (200 MHz, CDCl3, ): 1,08 (doublet, J 6.5 Hz, 3H); 1.2 to 2.1 (multiplet, 4H); 2,45 (singlet, 3H); 3,18 (multiplet, 1H); 4,54 (doublet, 2H); 4,89 (two doublet, JH-F50 Hz, 1H); 5,15 (two doublet, JH-F12 Hz, 1H); to 5.21-5,27 (multiplet, 3H); 5,9 (multiplet, 1H).

A mixture of 102 mg of N-allyloxycarbonyl derivative, 4,4 mg of tetrakis-(triphenylphosphine)-palladium, 4.4 mg of triphenylphosphine and 44.5 mg of 2-ethylhexanoic acid in 15 ml of anhydrous methylene chloride was stirred at 25oC for 21 hours Add methylene chloride, the organic phase is washed with 8% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is mixed with aqueous hydrochloric acid (pH 3), and then extracted with methylene chloride and the combined extracts dried over anhydrous sodium sulfate and concentrated to small volume. Add hydrogen chloride and diethyl ether to obtain the above compound (I, R H, R1H) (76 mg, yield 81). TCX on the plates Kieselgel (Merck F254) using the solvent system chloroform/methanol/water (65:30:10), gives Rf0,48.

Acting in a similar way, can be obtained the following compounds.

Hydrochloride 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R H, R1H)

H-NMR of the corresponding allyloxy (two doublet, JH-F3.6 Hz, J 19 Hz, 1H, H -10 EQ); 4,91 (two doublet, JH-F50 Hz, 1H, H-8); 5,14 (two doublet, JH-F12 Hz, 1H, H-7); 5,18-5,27 (multiplet, 3H, H-1' + -CH=CH2).

Hydrochloride 8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R H, R1OCH3).

H-NMR appropriate allyloxycarbonyl-derived says: H-NMR (200 MHz, CDCl3, among other things d ): 3,19 (doublet, J 19 Hz, 1H, H-10 ax); 3,48 (two doublet, JH-F3.6 Hz, J 19 Hz, 1H, H-10 EQ); 4,10 (singlet, 3H, OCH3).

Hydrochloride 8-fluoro-3'-deamino-4'-deoxy-4'- aminoadenosine (I, R H, R1OCH3).

H-NMR appropriate allyloxycarbonyl-derived says: H-NMR (200 MHz, CDCl3, among other things d ): 3,17 (doublet, J 19 Hz, 1H, H-10 ax); 3,52 (two doublet, JH-F3.6 Hz, J 19 Hz, 1H, H-10 EQ); 4,08 (singlet, 3H, OCH3).

Example 17. Hydrochloride 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R OH, R1H). According to the method described in U.S. Pat. USA N 4 122 076, a solution of 100 mg of the hydrochloride of 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-ötzi-aminocarnitine (IV, R1H, R2NH2), obtained as described in 2.5 ml of anhydrous methanol and 5 ml of dioxane is treated with stirring with a solution of 490 mg of bromine in 5 ml of chlorite is precipitated by adding diethyl ether. The crude reaction product is dissolved in a mixture of 5 ml of acetone and 1 ml of water and treated with 150 mg of sodium formiate. The reaction mixture was stirred at room temperature for 36 h, then add water and extracted with methylene chloride. The aqueous phase is mixed with 3 ml of 8-aqueous sodium bicarbonate solution and extracted with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, concentrated under vacuum to small volume and treated with a methanol solution of hydrogen chloride (pH 3.5), and diethyl ether, to obtain the above compound (I, R1H, R, OH) (77 mg, yield 75). TCX on the plates Kieselgel (Merck F254) using the solvent system chloroform/methanol/water (65:30:10), gives Rf0,31.

Acting in the same way and on the basis of the corresponding derivatives of daunorubicin (I, R H, R1H or OCH3), can be obtained the following compounds.

Hydrochloride 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-amino-doxorubicin (I, R OH, R1H). TCX on Kieselgel (Merck F254) using the solvent system chloroform/methanol/water (65:30:10), gives Rf0,34.

Hydrochloride 8-fluoro-3'-deamino-4'-deoxy-4'-aminooctanoic is Nol/water (65:30:10), gives Rf0,29.

Hydrochloride 8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R OH, R1OCH3). TCX on Kieselgel (Merck F254) using the solvent system chloroform/methanol/water (65:30:10), gives Rf0,27.

To obtain a pharmaceutical composition suitable for therapeutic use, an appropriate number of the current frame may be, for example, dissolved in bidistilled water for injection to a concentration of 1-10 mg/ml of the resulting solution can then be dried after adding the appropriate media (such as mannitol or lactose), or together, with or without suitable preserving drugs, and then divided into sterile containers (ampoules), ready for later use.

Annex 2.

Biological activity. The biological activity of the compounds.

1a: 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-amino-daunorubicin (I, R R1H),

1b: 8-fluoro-3'-deamino-4'-deoxy-4'-EPI-aminocarnitine (I, R H, R1OCH3)

1c: 4-dimethoxy-8-fluoro-3'-deamino-4'-deoxy-4'-EPI-amino-doxorubicin (I, R OH, R1H)

was tested in comparison with doxorubicin on the tx2">

Compounds 1a and 1c, as it turns out, are more cytotoxicity than the original compound, as against P388 and POYD small cell lung cancer sensitive to DXR.

This increased cytotoxicity, however, is much more evident if we consider the activity of these compounds against the corresponding DXR-resistant tumors (P388/DXR and POYD/DXR).

Activity in vivo (table. 2-4).

Against P388 leukemia and ovarian cancer cells both compounds 1a and 1c show antitumor activity, significantly higher than the antitumor activity, DXR, increasing the survival time of the mice and the degree of inhibition of tumor growth in smaller doses than the dose that use the original connection.

In adenocarcinoma of the lung H460, especially resistant to DXR, 1a and 1c show at least the same level of activity that the original compound, and the compound 1b was inactive.

1. 8-Foratricilegnousata General formula

< / BR>
where R is hydrogen or a hydroxy-group;

R1hydrogen, hydroxy or methoxy group and ~ NH2shows that aminosalicylic may be in the axial or Equatorial configuration,

or their farm is in the General formula I under item 1 or their pharmaceutically acceptable salts, characterized in that carry out the condensation of 8-forestration General formula II

< / BR>
with the compound of the formula IIIA

< / BR>
or IIIe

< / BR>
where X is chlorine or paranitrobenzoic;

R2triptoreline or allyloxycarbonyl group,

to obtain N-protected glycoside of General formula IV

< / BR>
where R1and R2have the above values, R2~indicates that the substituent R2is axial or Equatorial configuration, which removes the N-protective or trifluoracetyl preferably allyloxycarbonyl group, receiving the target product, where R is hydrogen, R1as described above, and, if necessary, converts the target product in its pharmaceutically acceptable salt, or, if necessary, bromilow specified glycoside of formula I, where R is hydrogen, or its pharmaceutically acceptable salt, followed by hydrolysis of the corresponding 14-bromo derivatives to obtain the desired product of formula I, where R is the hydroxy-group, which, if necessary, converted into pharmaceutically acceptable salt.

3. The method according to p. 2, characterized in that the condensation is carried out in the presence of condensing sulfonate of trimethylsilyl, paratoluenesulfonyl acid, triperoxonane acid, halides of boron, tin tetrachloride, titanium tetrachloride or acid resin amberlite type.

4. The method according to p. 3, wherein the process is conducted in an inert organic solvent in the presence of molecular sieves as a dehydrating.

5. The method according to PP.3 and 4, characterized in that the condensation reaction add pyridine, kallidin, N,N-dimethylaminopyridine, triethylamine.

6. The method according to PP.2 to 5, characterized in that N-trifluoracetyl group is removed under mild conditions of alkaline hydrolysis.

7. The method according to PP. 2 to 5, characterized in that N-allyloxycarbonyl group is removed by the action of organic complexes of Nickel or palladium.

8. The method according to PP.2 to 7, characterized in that the target product of the formula I, where R is hydrogen, emit in the form of hydrochloride.

9. The method according to PP. 2 to 8, characterized in that the hydrolysis of the corresponding 14-bromo derivatives is carried out using sodium formate.

10. The method according to PP.2 to 9, characterized in that the target product of the formula I, where R is the hydroxy-group, isolated in the form of hydrochloride.

11. Pharmaceutical composition having anti-Christ. mlely media characterized in that it contains as specified derivative compound of General formula I in an effective amount.

12. Derivatives of 8-(8H)-fluoro-7,10-dihydro-6.9.11-trihydroxy-5,12-naphthacenedione General formula II

< / BR>
where R1hydrogen, co3HE.

13. Derivative 8(8H)-fluoro-7,10-dihydro-6,7, (7H),9,11 tetrahydroxy-5,12-naphthacenedione General formula VII

< / BR>
where R1hydrogen, co3HE.

14. The compound of General formula IIIA

< / BR>
where X is chlorine or p-nitrobenzisoxazole;

R2trifurcated or allyloxycarbonyl.

15. The compound of General formula I

< / BR>
where X is chlorine or p-nitrobenzyloxy radical;

R2trifurcated or allyloxycarbonyl.

16. The method of obtaining compounds of General formula III(a,e)

< / BR>
where X is chlorine or p-nitrobenzisoxazole;

R2trifurcated or allyloxycarbonyl,

R2~indicates that this Deputy may be in axial IIIA or Equatorial configuration E, characterized in that a methyl-2,3,6-trideoxy--L-glyceroglycolipids-4-ulosa formula VIII

< / BR>
will predelay interaction with hydro is Tanglewood, then, after protection of the resulting amino group with trifluoracetyl group carry out the separation of 4-N-trifurcation of epimeres formula Ha

< / BR>
and Heh

< / BR>
or preferably after protection of the resulting amino group allyloxycarbonyl group carry out the separation of 4-N-allyloxycarbonyl of epimeres formula Chi

< / BR>
and Ixe

< / BR>
with subsequent transformation of each epimer Ha and Hye or Chi and XIe in the corresponding I-hydroxy formula XIIa

< / BR>
and XIIe

< / BR>
or He

< / BR>
and XIIIe

< / BR>
and target product, where X is chlorine or preferably para-nitrobenzisoxazole, and R the above values.

 

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