Derivatives texana, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Describes the new derivatives taxane General formula I, where R1and R2represent hydrogen atoms, or R1and R2together form a cyclic carbonate or cyclic thiocarbonate group of formula (a) or (b), R3is hydrogen, R4represents hydrogen or the residue azaserine formula II, where5is1-C5is an alkyl group or a phenyl residue, R6has the same meanings as R5or is tert-butoxypropan. New derivatives of taxane exhibit antitumor activity by inhibiting cell proliferation of normal and resistant cell lines, tumors and inducyruya apoptosis. These molecules, due to their basic character, you can enter after the formation of the salt in aqueous medium without the use of toxic surfactants. Describes the method of production thereof and pharmaceutical composition. 3 S. and 8 C. p. F.-ly, tabl.

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The present invention relates to a derivative taxane obtained from 10-deacetylbaccatin III, 14-hydroxy-10-deacetylbaccatin III, 19-hydroxy-10-deacetylbaccatin III and their complex EF is mi.

In EP 253738 describes Taxol derivatives having hydroxyl at positions 10 and 7 and keto in position 9, these derivatives can be replaced remaining azaserine in position 13; WO 94/25441 describes intraperitone that you can use as anticancer agents and their method of synthesis, in "Journal of the American Chemical Society", vol. 93, No. 9, pp. 2325-2327 describes the selection and study of Taxol derivatives having the properties of inhibiting tumors.

The new compounds contain the group pyrazoline, including carbon C2and C9. Esters of C13with isoprinosine chains functionalized C'3and NH, possess cytotoxic activity in cell lines the most common human cancers, as well as anticancer activity in vivo. Compounds of the invention are potent cytotoxic means, particularly active in cells that are resistant to known means, preventing cell growth, and are powerful tools that cause apoptosis in these cell lines, this activity is essential in cancer therapy.

Derivative of the present invention have the following General formula (1)

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where R1and R2 is alloctype, or R1and R2together form a cyclic carbonate or cyclic thiocarbonate group of the formula

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R3represents hydrogen or hydroxy;

R4represents hydrogen or the residue azaserine formula (2).

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where R5represents C1-C5-alkyl or C2-C5-alkenylphenol group or aryl residue, R6has the same meanings as R5or is tert-butoxypropan.

Aryl group is preferably phenyl group. Alkoxygroup preferably represents methoxy or ethoxypropan. Alloctype preferably represents acetochlor.

The compounds of formula (1) is obtained from taxane formula (3)

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where R1, R2, R3and R4are as defined above, by reaction with hydrazine in alcohol, preferably in methanol.

In the reaction are formed two diastereoisomer - and-configuration at C7that can be divided by fractional crystallization or, better, by chromatography using, for example, columns with silica gel and mixtures of ethyl acetate and hexane as eluents. In the reaction with hydrazine isomer obrashchaemogo invention. The reaction can be applied, except baccatin III or 14--hydroxyacetone III or the corresponding carbonates or thiocarbonates obtained by reaction with phosgene or thiophosgene in pyridine (patents Italy M195A000533 and M195001022), also for products already esterified C13such as paclitaxel, cephalomannine, docetaxel and their synthetic analogues. The above products, after removal of the acetate at C10treatment with hydrazine in methanol, are oxidized by copper acetate in a 10-dihydroprogesterone (see the above-cited patents Italy), which are directly converted into the corresponding derivatives of pyrazoline by treatment with hydrazine. The outputs of the conversion is almost quantitative in different stages. Derivatives pyrazoline can be used as such, and they have activity comparable to or higher than the activity of the original products, with regard to cytotoxicity. The obtained derivatives pyrazoline can be turned into dihydrobromide catalytic hydrogenation or they can be converted into derivatives of the nitrogen atom.

As an example, describes the cytotoxicity of some of the compounds obtained.

The results are shown in the table.

Compounds of the invention can be introduced in conventional pharmaceutical compositions, such as solutions of the active ingredient in polyoxyethylenated castor oil, available from, in particular, cations of metal, adversely affect the stability of existing (active) began, and their present, or in compositions containing other excipients, such as Polysorbate or phospholipids, forming with the latter liposomes. Compounds of the present invention can be also crushed together with the cyclodextrin oligomers, in particular - and - cyclodextrin, or to form a salt with pharmaceutically acceptable acids, in order to be fully introduced in the aquatic environment. The following examples illustrate the invention.

Example 1

Synthesis of 10-deazetil-10-dehydroacetic III or pyrazoline

To a suspension of 10-deazetil-10-dehydroalanine III (1 g, 1,845 mmol) in 15 ml of methanol add to 11.7 ml of 10% solution of hydrazine (to 31.5 mmol). The suspension is refluxed and after 10 minutes it becomes transparent. Reaction control TLC on silica gel, watching almost 2
O, acidified with HCl (100 ml) and extracted with EtOAc. The organic phase is dried on Na2SO4and concentrate to dryness. The residue is purified by chromatography on a column of silica gel (40 g silica gel, eluent hexane-ethyl acetate, 1: 1). Receive 687 mg-pyrazoline and 208 mg-pyrazoline having the following physico-chemical and spectroscopic characteristics:

-pyrazolin: so pl. 195oC,

MS+538,1H-NMR (CDCl3) H2 5.80 (d, J 8.6, H3 3.16 (d, J 8.6, H5 5.04 dd, J 9.5/4.5, H6a 2.43 ddd, J 13.5/9.5/4.5, H6 2.20 dd, J 13.5/13.5/4.5, H7 4.20 ddd, J 15.5/4.5/3.0, H13 4.69, H14 2.34 m, H16 1.23 s, H17 1.15 s, H18 1.66 s, H19 1.50 s, H20a 4.47 (d, J 8.6, H20b 4.33 (d, J 8.6, NH 6.44 br s, OH 2.33 brs/i,87 brs, Ac 2.26 s, Bz 8.14 brd 6.7.

-pyrazolin: so pl. 219-222oC, MS 538-,1H-NMR (CDCl3)

H26.04 d J 6.0, H3 3.71 (d, J 6.0, H5 4.93 br d, J 2.5, H6 2.06 td J14.0/14.0/2.5, 6' 1.85 m, H7 4.39 dd J14.0/4.2, H13 4.79, brdd, J 10.0/6.5, 14a 2.46 dd, J 15.0/10.0, 14b 1.88 dd J15.0/6.5, H16 1.33 s, H17 1.23 s, H18 1.74 brs, H19 1.70 s2O 4.38 s, NH 6.34 brs, OH 2.63/2.00, Ac 2.36 s, Bz 8.12 brd, /.6.

Example 2

Synthesis of 10-deazetil-10-dehydropolycondensation

400 mg 10-dehydroacetate (0.49 mmol) dissolved in 10 ml of methanol and add 10 mol. EQ. solution of NH2NH2(4.9 mmol, 1.5 ml) obtained by diluting 1 ml of pure NH2NH2in 10 ml of methanol. After 2 h the reaction mixture was diluted with water and 3 ml of diluted HCl and extracted with utilitech chromatographic through 10 g of silica gel, elwira a mixture of hexane/ethyl acetate, 1: 1, separating the fractions containing paclitaxel- -pyrazolin. Receive 250 mg of the compounds having the following characteristics: I. pl. 190oC,

MC 823 (M+NH4)+and1H-NMR and13C-NMR spectrum corresponding to this structure.

Example 3

Synthesis of 10-dihydro-13-(N-Boc-phenylisopropyl)-10-deacetylbaccatin III

1 g of docetaxel dissolved in 50 ml of dry methanol and added with stirring 3,71 g of finely ground copper acetate; the reaction mixture is stirred for 6 h at room temperature. The undissolved copper acetate is filtered off and the solution was diluted with water and extracted with ethyl acetate. The organic phase prototechno washed with diluted ammonia solution, then dried and concentrated to dryness. Get a pale yellow solid product with a yield of 85%, the corresponding 10-dihydro-13-(N-Boc-phenylisopropyl)-10-deacetylbaccatin III.

M+801.

Example 4

Synthesis of 13-(N-Boc-phenylisopropyl)-10-dehydro-10-deacetylbaccatin III-pyrazoline

390 mg 10 dehydro-13-(N-Boc-phenylisopropyl)-10-deacetylbaccatin III (0.49 mmol) dissolved in 10 ml of methanol and add 10 mol. EQ. solution of NH2NH2(4.9 mmol, 1.5 ml), the obtained Rabba is undertaken HCl and extracted with ethyl acetate. The organic phase is washed with counterflow, dried over sodium sulfate and evaporated to dryness. The remainder chromatographic through 10 g of silica gel with elution by the mixture hexane/ethyl acetate, 1: 1, separating the fractions containing docetaxel- -pyrazolin. Obtain 280 mg of the compound that has the following characteristics: I. pl. 190oC, MC 823 (M+NH4)+and1H-NMR and13C-NMR spectrum corresponding to this structure.

Example 5

Synthesis of 13-(N-Boc-3'-isobutyl)azaserine-10-dehydroacetic III-pyrazoline

To a solution of 100 mg of 13-(N-Boc-3'-isobutyl)isuserinrole III (0.12 mmol) in 2 ml of ethanol is added 10 mol. EQ. freshly prepared 10% solution of hydrazine in ethanol (1.2 mmol, 0,38 ml ethanol solution), then two times successively added 15 mol. EQ. of hydrazine with an interval of 12 hours between additions. After three days the deacetylation reaction is complete and the mixture is diluted with water and 2 ml of dilute HCl, and the whole mixture is extracted with ethyl acetate. The organic phase is washed with water until neutral, then dried and concentrated to dryness. The remainder chromatographic through a column of silica gel, elwira a mixture of ethyl acetate/hexane, 4:6. Obtain 67 mg of 13-(N-Boc-3'-isobutyl)azaserine-10-deacetylbaccatin III.

To a solution of brasego Cu(OAc)2and the whole mixture is stirred for 6 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate; the organic phase is washed with ammonia and then with water until neutral and concentrated to dryness. The residue is dissolved in 3 ml of methanol and add 20 mol. EQ. 10% solution of hydrazine in ethanol. The reaction mixture for two hours, refluxed, controlling the reaction TLC up until the reagents do not disappear. The reaction mixture was diluted with water and dilute hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness; the residue chromatographic on silica gel, elwira a mixture of hexane/ethyl acetate, 1:1. Get 29,2 mg-pyrazoline and 11 mg-pyrazoline.

Example 6

Synthesis of 13-(N-Boc-phenylisopropyl)-1,14-carbonate-10-dehydro-10 - deacetylbaccatin III-pyrazoline

To a solution of 100 mg of N-Boc-14-hydroxytrol 1,14-carbonate (0.11 mmol) in 3 ml MeOH added 10 mol. EQ. freshly prepared 10% solution of NH2NH2in ethanol (1.12 mmol, 0,36 ml ethanol solution. After 12 hours add an additional 10 mol. EQ. there was added 20 mol. EQ.). Reaction control TLC (Ex-EtOAc, 3:7). After 48 hours the reaction mixture rat, filtered, evaporated and the share of farm (column chromatography) (Ex-EtOAc, 6:4 and then 5:5) to give 30 mg of the raw product and 40 mg of 10-deacetylation.

To a solution of 40 mg of 10-deacetylation (0.05 mmol) in 3 ml of MeOH is added 15 mol. EQ. powdered Cu(OAc)2(0.69 mmol, 138 mg). The reaction, which lasts 24 hours, TLC control (Ex-EtOAc, 3:7). The reaction mixture was diluted with water and extracted with EtOAc (x 3); the organic phase is washed with a solution of NH3:H2O, 1:5, (x 2) and then with brine. The organic phase is evaporated, obtaining a pale yellow solid with almost quantitative yield.

The crude oxidation product using Cu(OAc)2dissolved in 2 ml of MeOH and added 20 mol. EQ. 10% solution of NH2NH2in ethanol (0.8 mmol, 0.25 ml ethanol solution). The reaction mixture is refluxed for 2 hours, the reaction control TLC (Ex-EtOAc, 3:7), then dilute with water, add 2-3 ml of diluted HCl and extracted with EtOAc (x 3). The organic phase is washed with brine, dried, mixed, filtered, evaporated and share the farm with Ex-EtOAc, 6:4/5:5, receiving 10.5 mg of pyrazoline (mixture ).

The example of the pharmaceutical composition 1

Receive pharmaceutical compositions the EL - 175 mg

Absolute ethanol - as you need to 0.4 ml

Example pharmaceutical compositions 2

Get a pharmaceutical composition in the form of a sterile injectable solution, consisting of:

The compound of example 2 to 6 mg

Cremophor EL - 0.5 ml

Anhydrous citric acid 2.0 mg

Absolute ethanol as needed up to 1 ml

Example pharmaceutical compositions 3

Get a pharmaceutical composition in the form of a sterile injectable solution, consisting of:

Connection example 3 - 4 mg

Emulphor EL - 0,1 ml

Absolute ethanol 0.1 ml

Saline - 1,8 MAV

1. Derivatives taxane formula I

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where R1and R2represent hydrogen atoms, or R1and R2together form a cyclic carbonate or cyclic thiocarbonate group of the formula

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R3represents hydrogen,

R4represents hydrogen or the residue azaserine formula II

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where R5represents C1- C5is an alkyl group or a phenyl residue;

R6has the same meanings as R5or is tertbutoxide.

2. Connection on p. 1, where R1, R2, R4represents a residue of formula II, where R5and R6represents phenyl.

4. Connection on p. 1, where R1, R2and R3represent hydrogen and R4represents a residue of formula II, where R5represents phenyl and R6represents tert.butoxy.

5. Connection on p. 1, where R1, R2and R3represent hydrogen and R4represents a residue of formula II, where R5is isobutyl and R6represents tert.butoxy.

6. Connection on p. 1, where R1and R2together form a cyclic carbonate group, R3is hydrogen and R4represents the residue azaserine, where R5represents phenyl and R6represents tert.butoxy.

7. Connection on p. 1, selected from: 7-deoxy-9-deoxo-7-hydrazine-9-ilidene-10-deazetil-10-dehydroacetic III (7 - and 7-isomers); 7-deoxy-9-deoxo-7-hydrazine-9-ilidene-10-deazetil-10-dehydroacetate; 13-(N-BOC-phenylisopropyl)-10-deazetil-10-dehydroacetic III; 13-(N-BOC-phenylisopropyl)-7-deoxy-9-deoxo-7-hydrazine-9-ilidene-10-deazetil-10-dehydroacetic III; 13-(N-BOC-3'-isobutylphenyl)-7-deoxy-9-deoxo-7-hydrazine-9-ilidene-10-deazetil-10-dehydroacetic III; 13-(N-BOC-phenylisopropyl)-7-deoxy-9-p. 1 for cytotoxic and antitumor drugs.

9. The method of obtaining compounds of formula I on p. 1 of taxane formula III:

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where R1, R2, R3and R4are as defined above, by reaction with hydrazine in alcohol.

10. The method according to p. 9, characterized in that as alcohol use methanol.

11. Pharmaceutical composition having cytotoxic and antitumor effect and containing as active ingredient the compound under item 1 in a mixture with a suitable carrier.

 

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