SK4894A3 - Derivatives of taxol analogues, preparation thereof and compositions containing them - Google Patents

Abstract

New derivatives of taxol analogues of general formula (I), their preparation and the compositions which contain them. In the formula (I): - Ar represents an aryl radical, - R represents a radical of general formula R7O- (II) in which R7 represents an optionally substituted alkyl radical or an alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, - R1 and R2, which are identical or different, represent a hydrogen atom or a radical of general formula (III) in which R3 and R4, which are identical or different, represent hydrogen or alkyl (optionally substituted by hydroxyl, carboxyl, alkyloxycarbonyl or a radical of formula (IV) in which R5 and R6, which are identical or different, represent hydrogen or alkyl or together form a 5- or 6-membered saturated or unsaturated heterocycle) or else R3 and R4 form a 5- or 6-membered, saturated or unsaturated heterocycle. The new products of formula (I) exhibit notable antitumour and antileukaemia properties. <IMAGE>

Description

Technical field

The present invention relates to novel derivatives of formula I analogs of taxol in general.

their preparation and compositions containing them. In the general formula I means:

Ar aryl,

R is a group of formula II

R ₇ 0/11 / in which R? represents a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 8 carbon atoms 6 carbon atoms or a bicycloalkyl group containing from 7 to 10 carbon atoms, which groups may optionally be substituted by one or more substituents selected from halogen atoms and hydroxyl groups, (C1-C4) alkyloxy groups of 1 to 4 carbon atoms wherein each alkyl group contains 1 to 4 carbon atoms, piperidine, morpholine or 1-piperazine residues optionally substituted at the 4-position with an alkyl group containing 1 to 4 carbon atoms, or a phenylalkyl group having an alkyl group 1 to 4 carbon atoms, further from cycloalkyl groups; C 3 -C 6 -cycloalkenyl, C 4 -C 6 -cycloalkenyl, phenyl, cyano, carboxyl or alkyloxycarbonyl, wherein the alkyl moiety contains 1 to 4 carbon atoms, or phenyl optionally substituted by one or more atoms or groups selected from halogen atoms and alkyl groups containing from 1 to 4 carbon atoms or alkoxy groups containing from 1 to 4 carbon atoms, or a nitrogen heterocycle residue, saturated or unsaturated, containing 4 or 6 members and optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms, R 1 and R 2 substituents ₂ , same or different, represents a hydrogen atom or a group of formula III

NCO (111) in which the substituents R 5 and R ₄ , the same or different, denote a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms, which is optionally substituted:

a / a hydroxyl, carboxyl, alkyloxycarbonyl group, the alkyl component of which contains 1 to 4 carbon atoms and which is optionally substituted by a phenyl group, b) a group of the formula IV

R 5 -N (IV) wherein R 5 and R 5, the same or different, represent a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms, or R 5 and R 6, taken together, form a nitrogen atom to which are bonded, saturated or unsaturated, a five- or six-membered heterocycle optionally containing a second heteroatom selected from nitrogen atoms optionally substituted by an alkyl group containing 1 to 4 carbon atoms or a benzyl group, oxygen or sulfur, or substituents R ₃ and R ₃ , taken together, form with the nitrogen atom to which they are attached, saturated or unsaturated, a five- or six-membered heterocycle optionally containing a second heteroatom selected from nitrogen atoms optionally substituted with an alkyl group containing 1 to 4 carbon atoms or a benzyl group, oxygen or sulfur, it being understood that at least one of R @ 1 and R @ c represent a group of formula III.

Preferably, Ar is phenyl or alpha or beta naphthyl optionally substituted by one or more atoms or groups selected from halogen / fluorine, chlorine, bromine or iodine atoms or groups such as alkyl, alkenyl, and alkyl. 1-, aryl-1-, aralkyl-, alkoxy-, alkylthio-, aryloxy-, arylthio-, hydroxy-, hydroxyalkyl-, mercapto-, formyl-, acyl-, acylamino-, arylamino-, and 1-alkoxycarbonylamines; nano-, amino-, alkylamino-, dialkylamino-, carboxy-, and 1-alkoxycarbonyl-, carbamoyl-, diabenzylcarbamoyl-, cyano-, nitro- and tri-fluoromethyl groups, it being understood that alkyl groups and the alkyl moieties of other groups contain 1 to 4 carbon atoms and that the alkenyl and alkynyl groups contain 3 to 8 carbon atoms and that the aryl groups are phenyl or alpha or beta-naphthyl groups.

More preferably, Ar is a phenyl group, optionally substituted with one or more atoms or groups, identical or different, selected from halogen atoms and alkyl-, and 1-alkoxy, amino-, alkylamino-, dialkylamino-, acylamino-, alkoxycarbonyl amine and tri fluoromethyl trypt.

Even more preferably, Ar is a phenyl group optionally substituted by a chlorine or fluorine atom, or an alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (tert-butoxycarbonylamino) group.

SUMMARY OF THE INVENTION

According to the invention, the novel derivatives of the t-axol analogues of the formula I can be obtained by treatment with amines of the general formula V

(V) wherein R 5 and R 6 have the taxane derivative of formula VI as defined above, to

wherein R and Ar are as defined above, to form a compound of formula VII 'O'

(VII),

R-CONH

Ar

OH wherein R and Ar are as defined above, G 1 and G c are each a group of formula II or a protecting group CCl 3 CH 2 OOC-, wherein at least one of G 1 and G 2 is understood to be a group of formula III, desirably, multiple protecting groups CCl 5 CHOCOCO or replacement of one hydrogen atom.

Generally, the action of the amine of formula (V) on the taxane derivative of formula (VI) is carried out in a non-reactive organic solvent such as a halogenated aliphatic hydrocarbon such as methylene chloride at a temperature ranging from 0 ° C to the boiling point of the reaction mixture. To avoid danger to the 7-position, is particularly advantageous to operate in methylene chloride at a temperature below 50 ⁰ C. When working at a higher temperature than 50 ° C, optionally in the presence of a sufficient excess of the amine V, it forms a mixture of products of formula VII wherein one of G, or G; is a group of formula III, or wherein each of G ₁ or G ₂ is a group of formula III.

The replacement of G 1 or G 2, not acetic, in the range of the protecting group represented by the substituents, is usually carried out by treatment with zinc in the presence of methanol at a temperature of up to 80 ° C.

The products of formula (I) may be isolated from their mixtures by preparative chromatography on suitable carriers.

The products of formula (I) obtained by the process of the invention can be purified by physical methods such as crystallization or chromatography on a suitable support.

The product of formula (I) may optionally be converted into an addition salt with a mineral acid (hydrochloric, sulfuric, nitric or phosphoric) or with an organic acid (acetic, oxalic, maleic or fumaric).

The products of formula (VI) can be obtained by the processes described in European Pat. file no. EP-0 253 738 and EP-0 253 739.

The products of formula I, and in particular those in which R represents a tert-butoxy group, exhibit remarkable biological properties.

In vitro, the measurement of biological activity is performed on an isolated porcine brain board by the method described by M.L. Shelanski et al., Proc. Natl. Acad. Sci. United States, 7 0. 765-768 / 1 9 7 3 /. The study of depolymerization of microtubules in tubulin is carried out by the method of G. Chauviere et al., C. R. Acad. Sci., 293. Series II, 50-1503 (1989-1991). In this study, derivatives of Formula I have been shown to be at least as effective as taxol.

In vivo, derivatives of Formula I have demonstrated efficacy in mice inoculated with melanoma B16 at doses ranging from 1 to 10 mg / kg by intraperitoneal administration as well as in mice. other solid and similar tumors.

In addition, the derivatives of the formula I are better soluble in water than the taxol derivatives or taxane derivatives which are the subject of European Pat. file no. EP-0 253 738.

The following examples illustrate the invention.

EXAMPLES In an embodiment of the invention

Example 1

In a flask equipped with a magnetic stirrer with a condenser was placed 365 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20- epoxy-1beta-hydroxy-9-oxo-7beta, 10beta-bis - [(2,2,2-trichloroethoxy) carbonyloxy] -11-taxen-13alpha-1, dissolved in 10ml of methylene chloride. Add 80 μΐ of 3-methylaminopropyl amine. The reaction mixture was heated at 40 ° C under argon for 4 hours. The solution is washed twice with 10 ml of water each time. After drying and evaporation of the solvent, the obtained residue is purified on a thick layer of diatomaceous earth by elution with a mixture of methylene chloride and methanol (8: 2 by volume). 250 mg of 3-tert-butoxycarbonyl-amide-2-hydroxy-3-phenylpropionate (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-9-oxo-10beta are obtained. - (3-dimethylaminopropyl) aminocarbonyloxy-7beta - / (2,2,2-trichloroethoxy) carbonyloxy] -11-taxen-13-a1-phenyl, whose structure is confirmed by the NMR spectrum determined in deuterated chloroform at which chemical transformations are expressed in ppm and the constant J in Hertz:

1.16 (s, 3H); 1.25 (s, 3H); 1.35 (s, 9H); 1.83 (s, 3H); 1.93 (s, 3H); 2.26 (s, 6H); 2.38 (s, 3H); 3.25 (m, 2H); 3.93 / d, J =

7.1, 1H); 4.16 and 4.33 / 2d, J = 9, 2H); 4.62 /with , br, 1 H /; 4.73 and 4.99 (2d, J = 12, 2H); 4.96 (d, J = 9, 1H); 5.29 / d, J = 9, 1 H /; 5.47 (d, J = 1H); 5.54 / m, 1H /; 5.66 / d, J = 7 1 H /; 6.19 / t, J = 9, 1H /; 6.29 (s, 1H); 7.37 / 5H /; 7.49, 7.62 s 8 , 09 (5H). To a solution of 137 mg product that was higher obtained. in acetic acid / methanol / 1 1 Obj./, the was added 130 mg zinc dust. The reaction mixture was stirred stir at 60 ° C 1 ho-

Dinu. After filtration and evaporation to dryness, the residue is taken up in water and extracted with ethyl acetate. After separation and drying, the organic phase is evaporated to dryness. The residue obtained is purified by chromatography on kieselguhr and eluted with methylene chloride / methanol (8: 2 v / v). 73 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-beta, 7beta-dihydroxy-9-oxo are thus obtained. -10beta- (3-dimethylaminopropyl) aminocarbonyloxy-11-taxen3

-I3alpha-y lu having the following characteristics:

JV-spectrum (ethanol): λ max - 230 nm (Σ 12,700) λ max - 275 nm (Σ 1040);

IR spectrum (methylene chloride): main characteristic absorption bands at 3400, 2960 and 1729 cm ^-1 ; proton NMR spectrum:

1 18 / s, 3 H /; 1.23 (s, 3H); 1.33 '/ s, 9 H /; 1, 66 (s, 3H); 1.87 /with 3H; 2, 28 /with , 6H /; 2.38 (s, 3H); 3, 20 / m, 2 H /; 3.78 / d, J = 7 1 H /; 4.17 a 4, 31/2d, J -8, 2H); 4.43 / dd, J = 6 and 12, 1H); 4J 62 / S, š i r mesh 1H /; 4.97 / d, J = 9 1 H /; 5.2 Δ (d, J = 9, 1H); 5 54 / d, J = 9, 1 H /; 5.66 / d, J = 7, 1H); 6.21 / M 2 H /; 7.39 (5H); 7 51, 7, 62 a 8.11 / 5H /;

mass spectrum (FAB): 936 (M @ +).

To a solution of the product obtained above in 0.5 ml of ethanol is added 0.780 ml of a 0.1 M hydrochloric acid solution. The reaction mixture was evaporated to dryness and then lyophilized. There was thus obtained 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7beta-dihydroxy-9-oxo- hydrochloride. 10-beta- (3-dimethylaminopropyl) aminocarbonyloxy-11-taxen-13a-fayl having the following characteristics:

optical rotation: [.alpha.] D @ ² = -29 ° / c = 0.4; ethanol /; proton spectrum NMR / CDCl3 p-CDsOD /: 1.16 (s, 3H); 1.21 (s, 3H); 1.40 / s, 9 H /; 1.66 (s, 3H); 1.93 (s, 3H); 2.38 / s, 3 H /; 2.83 (s, 6H); 3.16 (m, 2H); 3.81 / d, J = 7.1, 1H); 4.23 and 4.31 / 2 d, J = 3 , 2H /; 4. 38 (m, 11-}); 4.5 (m, 1H); 4.99 (d, J = 9, 1H); 5.16 / s , 1H); 5 Δ 6 (d, J = 7.1, 1H); 6,16 / t, J = 9, 1H); 6.26 / s, 1H /; 7.37 / 5H /; 7 52, 7.70 and 3.09 (5H). Example 2 To the solution 4.63 g 3-tert .-Butoxycarbonylamino-2-hydroxy-3-

-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxene -13alpha-yl in 100 ml of acetonitrile, maintained under argon, is added 0.50 ml of 3-dimethylaminoprog pylamine. The reaction mixture is heated to about 60 ° C with stirring for 3 hours, then cooled to about 20 ° C and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 5.3 g of a white foam are obtained, which is purified by column chromatography (4 cm diameter) with 150 g of diatomaceous earth (0.063-0.2 mm grain size), eluting with methylene chloride / methanol (95: 5 v / v). ./ and 100 ml fractions are collected. Fractions 1 to 10 are discarded, then chromatography is continued and eluted with methylene chloride / methanol (80: 20 v / v). Fractions 17 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. There was thus obtained 2.57 g of a mixture of the two derivatives substituted in the 10-position and 7 of the (3-dimethylaminopropyl) carbamoyloxy] -group.

The mixture thus obtained is separated by high performance liquid chromatography onto 400 g of support, the preparation of which is described below, placed in a column 25 cm long and 6 cm in diameter, using hexane / ethanol / 80: 20: 2.5 by volume as the mobile phase. ./ in an amount of 45 ml / ml n. Gradual elution yields:

0.46 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta - / (3-dimethylaminopropyl) carbamoyloxy] -9-oxo-10beta- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl as a white foam,

0.81 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-10beta - / ( 3-dimethylaminopropyl) carbamoyloxy] -9-oxo-beta- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl as a white foam.

The carrier can be prepared as follows:

In a six-liter three-necked flask was suspended 600 g of aminopropyl 1 Cr / 100 Å -10 μτη - NH =; Macherey-Nage 1 / in 2 liters of the 1 for mamidu. 95 g of 11-N-tert-butoxycarbonylaminoundecanoic anhydride are added and the reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C. The diatomaceous earth is filtered off and washed successively twice with 1500 ml of methylene chloride and then with 0 ° C. This is obtained

The diatomaceous earth BOC-C11-C3 structure confirms elemental analysis is:

twice each with 1500 ml of dimethylformamide. The washed diatomaceous earth was resuspended in 2 liters of dimethylformamide and 95 g of 11-N-tert-butoxycarbonylaminoundecanoic anhydride was added, followed by stirring at about 20 ^° C for 18 hours.

The diatomaceous earth is separated by filtration, washed successively with 600 ml of methylene chloride, twice with 600 ml of tetrahydrofuran, twice with 600 ml of methanol and twice with 600 ml of diethyl ether, then dried under reduced pressure at a temperature of about 610 g of diatomaceous earth. by name in the form of a white powder, the IR spectrum of which: C = 8.8%; H = 1.7%; M = 1.2% (found).

607 g of BOC-C11-C3 diatomaceous earth in 2 liters of methylene chloride and 69 ml of pyridine are suspended in a six-liter three-necked flask. 530 ml of methylethylchlorosilane are added dropwise, then the reaction mixture is stirred for 16 hours at a temperature in the region of 20 ° C. The solid obtained is filtered and washed successively two times with 1 liter of methylene chloride, two times with 1 liter of methanol, two times with 1 liter of tetrahydrofuran, two times with 1 liter of methylene chloride and two times with 1 liter of diethyl ether. under reduced pressure at a temperature of about 20 ° C. 712 g of diatomaceous earth, known as diatomaceous earth BOC-C11-Cs-OSi / CH3 / 2- / CH2 / 7 CH3, are obtained in the form of a white powder whose structure is confirmed by an infrared spectrum and whose elemental analysis is: C = 12, 1%; H = 2.4%; N = 1.0% (found).

711 g of BOC-C11-C3-0-Si (CH3) and (CH2 ₎ 7CH3 diatomaceous earth are suspended in 2200 ml of a 6% ₍ v / v) trifluoroacetic acid solution in methylene chloride in a six-liter three-necked flask. The reaction mixture was stirred at about 20 ° C for 5 hours.

The diatomaceous earth is filtered off and washed successively two times with 1 liter of methylene chloride, two times with 1 liter of methylene chloride with isopropylethylamine (70: 30 v / v), 1 liter of methylene chloride, two times with 1 liter of tetrahydrofuran, two times with 1 liter of methanol and two times. After 1 liter of diethyl ether, it is dried under reduced pressure at a temperature of about 50 ° C. The washed and dried diatomaceous earth is again suspended in 2 liters of a six-liter solution of three fluoro acetic acid in methylene chloride.

at a temperature of about 20 ° C. rinse two times for 1.5

The reaction mixture is stirred for 16 hours. The diatomaceous earth is filtered off and successively with a liter of methylene chloride, twice with 1 liter of a mixture of methylene chloride and diisopropylethylamine (70).

1.5 liters of methylene chloride, twice with 2 liters of tetrahydrofuran, twice with 2 liters of methanol and twice with 2 liters of diethyl ether, then dried under reduced pressure and at a temperature of about 50 ° C. 607 g of diatomaceous earth, known as diatomaceous earth C 1 -C 3 -OSi / CH 3/2 / CH c / 7 CH 3, are obtained in the form of a white powder whose structure is confirmed by infrared spectrum and tare analysis is: C = 8, 8%; H = 1.7%; N = 1,3%

In a four-necked three-necked flask, 400 g of C 11 -C 8 -O-Si / CH 3/2 / CH 2 / CH ₃ Cl 3 are suspended in 1800 ml of dimethyl formamide. 42 g of 3,5-di-itrobenzoyl-D-phenylglycine and 30 g of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added and the reaction mixture is stirred for 16 hours at a temperature of about 20 °. C. The diatomaceous earth is filtered off and washed successively twice with 1 liter of methylene chloride, twice with 1 liter of tetrahydrofuran, twice with 1 liter of methanol and twice with 1 liter of diethyl ether. The washed diatomaceous earth is resuspended in 2 liters of diethyl formide, 30 g of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline and 42 g of 3,5-dinitrobenzoyl-D-phenylglycine are added and the reaction mixture is stirred at about 20 ° C for 5 hours. The diatomaceous earth is filtered off, washed successively twice with 1 liter of dimethyl formamide, twice with 1 liter of methanol and twice with 1 liter of diethyl ether and dried under reduced pressure at a temperature of about 140 ° C to 434 g of diatomaceous earth, called DNS-D- Phg-C 11 C 3 -O-Si / CH 3/2 / CH 2/7 CH 3, in the form of a white powder whose structure is confirmed by the infrared spectrum and whose elemental analysis is: C = 12.3%; H = 1.8%; N = 2.1% (found).

In a three-necked flask štvor1 itrovej was suspended 434 g of silica gel DNB-D-Phg-C11-C-O-Si / CH / p / CHCl / 7 CH ₃ in 1.3 L of methylene chloride, 100 ml of di methyl 1okty 1metoxys the anus 1 and the reaction mixture is stirred at a temperature of about 20 ° C for 54 hours. Crepe is obtained

The 2 mins were filtered and washed successively twice with 1 liter of methylene chloride, twice with 1 liter of methanol, twice with 1 liter of tetrahydrofuran and twice with 1 liter of methylene chloride, then dried under reduced pressure at about 140 ° C. This gives 425 g of diatomaceous earth, known as diatomaceous earth DNB-D-Phg-C 1 - C3-OSi / CH 3 / and / CH 2/7 CH, as a white powder, the structure of which is confirmed by an infrared spectrum. elemental analysis is: C = 12.7%; H = 1.9%; N = 2.0% (found).

425 g of diatomaceous earth DNB-D-Phg-C 1 -C 3 -O-Si / CH 3/2 / CH 2/7 CH 3 re-octylated in 1.3 liters of methylene chloride are suspended in a 4-neck three-necked flask. 545 ml of trimethylsilyl iodide are added dropwise and the reaction mixture is stirred for 15 hours at a temperature of about 20 ° C. The solid obtained is filtered off and washed successively twice with 1 liter of tetrahydrofuran, twice with 1 liter of methanol, twice with 1 liter of acetone and twice with 1 liter of methylene chloride, then dried under reduced pressure at a temperature of about 20 ° C. 431 g of diatomaceous earth, called diatomaceous earth DNB-D-Phg-C11-C3-Q-Si / CH3 / 2 / CH2 / 7CH3, are obtained in the form of a white powder whose structure is confirmed by an infrared spectrum and whose elemental analysis is: C-13 , 7%; H = 2.2%; N = 2.0% (found).

11-N-tert-butoxycarbonylaminoundecanoic anhydride can be prepared as follows:

To a solution of 30.1 g of 11-N-tert-butoxycarbonyl-amine inoundecanoic acid in 480 ml of ethyl acetate, maintained at about 50 ^° C, is added a solution of 10.63 g of Ν, ,6-dicyclohexylcarbodiimide in 120 ml of ethyl acetate. The reaction mixture is stirred at about 5 ° C for 1 hour, then at about 20 ° C for 16 hours. The precipitate was filtered off and washed with 30 ml of ethyl acetate. The filtrate was evaporated under reduced pressure at 30 ^° C. The residue was dried under vacuum at about 30 ° C. 31 g of 11-N-tert-butoxycarbonyl amine noundecanoic anhydride are obtained, m.p. 58 ° C.

11-N-tert-butoxycarbonylaminoundecanoic acid can be prepared by the method described by J.T. Spar Row, J. Org. Chem.

3

41, 1350 (1976).

A solution of 140 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-10beta - / (3-dimethylaminopropyl) carbamoyloxy] -9-oxo-7beta- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl, obtained above, in a mixture of 8 ml of methanol with 8 ml of acetic acid is heated to stirring at a temperature of argon 60 ° C and 1.2 g of zinc dust is added. The reaction mixture was then stirred at 60 ° C for 1.5 hours, cooled to about 20 ° C, and filtered through a celite pad. The filter was washed three times with 5 methylene chloride and the combined filtrates were evaporated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C.

5 ml of water and 5 ml of ethyl acetate are added to the residue. The aqueous phase was separated and extracted three more times with 5 ml of ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa) at 40 ° C. 19 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta-dihydroxy-10beta - / (3- dimethylaminopropyl) carbamoyloxy] -9-oxo-11-taxen-13alpha-yl, in the form of a white foam having the following characteristics: NMR / 400 MHz; CDC1 ₃ /:

delta (ppm) : 1.30 / 2S, 3H each: -CHs 16 and 17); 1.38 / s, 9H: C / CH / and /; 1,70 / s, 3H: - CH 18 or 19); 1.90 /with , 3H: --CH3 18 or 19); 1.90 [m, 2H : - NHCHíCHcCHsN / CH / s] ; 2.2 to 2.90 [m, 15H: -] / CH ₂ / -6 -CHc- 14 -ch ₌ n / ch ₃ / =, -m / ch 3 / = , -COCH 3]; 3.2 and 3.4 [2m, 2H: NHCH aCH = N _CH2 / _CH3 / =]; 3.8 / d, 1H: -H3]; 4.2 and 4.34 / AB, 2H : -CH = - 20 /; 4.45 / d d, 1H s J = 1 1 and 7: -H7 /; 4.66 m / z, 1H : -H2 '/; 5.0 / b d, 1H, J = 9 -H 5; 5.3 / bs, 1 H: - H 3 '; 5 6 [bd, 1 H -NHCH = CH = CH ₃ N / CH ₃ / d ; 5.68 / D, 1 H, J = 7: -H 2; 6.25 / m, 2H: -H 13 and -H 10); 6.4 [bs, 1 H:

--NHCOOC / _CH3 / _3]; 7,2 to 7,4 / mt, 5H, C ₅ H 3 _e '/; 7.5 [t, 2H, J = 7.5: --COOC6H5 (-H3 and -H5)]; 7.64 [t, 1H: --COCO (C6H4) --H4]; 8.12 [d, 2H: -OCOCeH5 (-H2 and -H6)].

Solution 59 mg of 3-1e trans-butoxycarbonylamino-2-hydroxy-3-phenyl-4

(2R, 3S) 4-Acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-10beta - [(3-dimethylaminopropyl) carbamoyloxy] -9-oxo-10beta-] 2,2,2-nylpropionate The trichloroethoxy / carbamoyloxy-11-taxen-13alpha-yl obtained above, in a mixture of 6 ml of methanol and 6 ml of acetic acid, is heated with stirring under argon to a temperature of about 60 DEG C. and 1.2 g of zinc dust are added. The reaction mixture was then stirred at 60 ° C for 1.5 hours, cooled to about 20 ° C, and filtered through a celite pad. The filter is washed three times with 5 ml of methylene chloride and the combined filtrates are evaporated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. 5 ml of water and 5 ml of ethyl acetate are added to the residue. The aqueous phase is separated and extracted three more times with 5 ml of ethyl acetate each time. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 9 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1, 10beta-dihydroxy-7beta - / (3) are obtained. -dimethylaminopropyl) carbamoyloxy / -9-oxo-11-taxen-13a-1-y-1 in the form of a white foam having the following characteristics:

spectrum NMR / 4 0 0 MHz; CDC 1 3 /: Delta (ppm): 1, 30 / 2S, 3H every : -CH ₃ 16 and 17); 1.36 / s , 9H : -C (CH3 ₎ / a /; 1, 82 /WITH , 3H: -CH ₃ 18 or 19); 1 9 5 / s 3H: -CH ₃ 18 or 19 /; 1, 88 [m , 2H: - NHCH ₂ CH = CH = N / CH 3 / -]; 2 2 to 2.70 [m , 15H - / CH = / -6. -CH ₌ - 14, -CH 2 N (CH 3) =, -N / CH 3 / =, -COCH ₃ ]; 3.15 a 3, 3 [2m , 2H : -NHCH CHcCH ₂ N ₂ / CH _3/3] ; 4.0 / d, 1H : --H3; 4.2 and 4.38 / AB , 2H : -CH = - 20 /; 4.68 / bs, 1 H; - H 2 '/ 4.96 / bd , 1H, J = 9 Hz: -H 5 /; 5.3 / bs, 1H: -H 3 ' /; 5.40 / O, 1H, J = 11 and 7 : -H 7 /; 5, 5 [s + bs, 2H: -H 10 and - NH CH ₃ CH CH ₃ - N / CH _3/2] ; 5.7 [d + bs, 2H : -H 2 and -NHCOOC / CH 3/3 ]; 6.22 / Bt. 1H: --H 13 /; 7.2 to 7 4 / mt, 5H : -C 6 H 3 '; 7 53 [t, 2H, J = 7.5: -OCOCeHs / -H 3 and -H 5]; 7.65 [t, 1H: "OCOCeH S / H

4 /]; 8.12 [d, 2H: -OCOCeH5 -H2 and -H6]].

Example 3

5

By analogy to Example 2, but starting at 6.95 g of 31-tert-butoxycarbonyl-amide-2-hydroxy-3-phenylpropionate - [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta-20epoxy-1 -hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13a-phthalene and 0.94 g of 3- (4-methylpiperazin) (propylamine), after purification by high-performance liquid chromatography, using methanol-1-ethanol-hexane-methylene chloride (10: 10: 80: 2 vol.) as the mobile phase, yields:

1.37 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-10beta - {[3- (4-Methylpiperazinyl) propyl] carbamoyloxy} -9-oxo-7beta- [2,2,2-1] chloroethoxy] carbonyloxy-11-taxen-13alphayl as a white foam, and

2.17 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta - {/ 3- (4-methylpiperazinyl) propyl (carbamoyloxy) -9-oxo-10beta- [2,2,2-trichloroethoxy] carbonyloxy-11-taxen-13alpha-yl as a white foam.

The obtained 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-10beta - {[3- (4-methylpiperazinyl)]] propyl / carbamoyloxy} -9-oxo-7beta- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl was converted by treatment with zinc in a mixture of methanol and acetic acid in 3-tert-butoxycarbonylamino-2-hydroxy 3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta-dihydroxy-10beta - {[3- (4-methylpiperazinyl) propyl] carbamoyloxy} 9-oxo-11taxene -13alpha-yl as described in Example 2 for 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1- 10.beta.-hydroxy - / (3-dimethylaminopropyl) carbamoyloxy-9-oxo-7.beta / 2,2,2-trichloroethoxycarbonyl / carbonyloxy-11-taxen-13.alpha.-yl.

The product obtained has the following characteristics: NMR / 400 MHz spectrum; CDCl /:

delta / ppm / 1.18 / s, 3H: _-CH3 16 or 17 /; 1.27 / s, 3H:

- CH 16 or 17); 1.33 (s, 9H: --CH3); 1.7 / s, 3H: _-CH3

19 /; 1.6 to 1.95 / mt, 3H: CH -OCONHCHz _of CH = N and _ε - / CH / 6-H /;

1, 88 /with , 3H: --CH3 18 /; 2.2 until 2, 7 / mt, 13H: _CH2 N / CH ₂ ch ₂ / - cNCH 3, - CH ₂ - 14 a - (C H) -H 6 /; 2.2 9 (s, 3H: = NCH3 ₎ ; 2.4 /with , 3H: -COCHs /; 3.2 to 3.45 / mt, 2 H : -OCONHC H ₂ CH ₂ CH s N = /; 3, 8 / D 1H, J = 7: -H 3]; 4.18 and 4.31 / 2 d, 1H each, J = 8 : - ch ₂ - 20 /; 4.44 / dd, 1H, J = 11 a 7: -H 7 /; 4.36 / mf, 1H: -H 2 '/; 4.97 / d broad, 1H , J = 10: - H 5 /; 5.27 / d broad, 1H, J = 9.5 : -H 3 ' / - 5.4 / d 1 H, J = 9, 5 NHCOOC / CH / p /; 5.67 / D 1 H, J = 7 : -H 2 /; 6.20 / s, 1H: -H 10 /; 6.25 / mt, 1H: --H 13 /; 7.0 / mf, 1 H : -NHCHsCH ₂ CH ₂ N = /; 7, 25 to 7.45 / mt, 5H: --C 6 H 5 3 '/; 7.51 / T 2H, J = 9: -OCOCsH 5 / ~ H 3 and -H 5 //; 7.62 / t, 1 H, J = 8 : -OCOCc H5 / -H4 /; 8.13 / d 2H, J = 8 : -CO 2 C 5 H 5 / -H 2 and H 6 //

To a solution of 5 mg of 3-tert-butoxycarbonyl-amide-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1,7beta-dihydroxy-10beta- The {[3- (4-methylpiperazinyl) propyl] carbamoyloxy} -9-oxo-11 -taxen-13alpha-yl obtained above in 0.1 ml of 0.1 N hydrochloric acid solution is added 0.2 ml distilled water and the solution was lyophilized. 5 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1,7beta-dihydroxy-10beta dihydrochloride are obtained. - {[3- (4-Methylpiperazinyl) propyl] carbamoyloxy} -9-oxo-11 -taxen-13a-phyl, having the following characteristics:

NMR spectrum / 400 MHz; D ₂ 0 + Σ CDaCOOD /:

delta / ppm / 0.88 / s, 3H: _-CH3 16 or 17 /; 0.93 (s, 3H: --CH3 16 or 17); 1.09 (s, 9H: --C (CH3) 3); 1.4 / s, 3H: _-CH3 19 /; 1.4 to 1.9 (mt, 5H: -OCONHCH ₂ CH ₂ CH ₂ N =, -CH ₂ - 14 and - (CH ₂ )

-H 6; 1.66 / s, 3H: -CH ₃ 18; 2.09 (S, 3H: --COCH3 ₎ ; 2.32 (mt, 1H: - (CH) - H 6); 2.81 / s, 3H: -NCH3; 2.9 to 3.2 and 3.4 up to 3.55 / 2 mt resp. 4H and 9H: -OCONHCH ₂ CH ₂ CH ₂ N / CH ₂ CH _2/2 NCH ₃ and -H 3; 4.01 / mt, 3H : -CH ₂ 20 and -H 7; 4.36 / d, 1H, J = 6.6 Hz -H 2 '; 4.6 to 4.8 / -H 3 ': no signal for drowned solvent signal /; 4.84 / d broad, 1H, J = 9: -H 5; 5.34 (d, 1H, J-7: -H 2); 5.82 / t, 1H, J = 9: -H 13]; 6.01 / s, 1H : -H 10; 7.03 / t, 1H , J = 7: - C 6 H 3 '- H 4'; 7 13 / d, 2H J 8: -CeH _the 3 '/ - H 2, and H 6 //; 7.2 / t, 2H, J = 8: -C ₆ H _s 3 '- H 3 and -H 5 //; 7.38 / t 2H, J = 9: -CO 2 C 5 H 5 / -H 3 a H 5 //; 7.51

7 / t, 1H, J = 8: _{--OCOC6 H5} / H 4 //; 7.8 (d, 2H, J = 8: -OCOC6H5) -H and -H6].

The obtained 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta - {[3- (4- methylpiperazinyl) propyl (carbamoyloxy) -9-oxo-10beta- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl was treated with zinc in a mixture of methanol and acetic acid in 3-tert- butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,10beta-dihydroxy-7beta - {[3- (4-methylpiperazinyl) propyl] carbamoyloxy -9-oxo-11-taxen-13alpha-yl as described in Example 2 for the preparation of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha benzoyloxy-5?, 20-epoxy-1-hydroxy-10.beta. - / (3-dimethylaminopropyl) carbamoyloxy / 9-oxo-7.beta / 2,2,2-trichloroethoxycarbonyl / karbony1oxy-11-taxen-13.alpha.-yl.

The product obtained has the following characteristics: optical rotation: / a / D = ² ° -14 ° / c = 0.41; methanol /; NMR spectrum / 400 MHz; CDC1 ₃ /:

delta (ppm); 1.13 / s, 3H: _-CH3 16 or 17 /; 1.24 / s, 3H:

-CH ₃ 16 or 17); 1.37 (s, 9H: --C (CH3 _{) 3} ); 1.6 to 2.0 / mt, 3H: -OCONHCH ₂ CH ₂ CH ₂ N = a - / CH / H 6; 1.84 / s, 3H: _-CH3 19 /; 1.92 / s, 3H: _-CH3 18 /; 2.3 / d, 2H, J = 8.5: CH _2-14 /; 2.33 / s, 6H: _NCH3 and = -COCH ₃ /; 2.3 to 2.8 / mt, 11H: _CH2 N / CH _2? H ₂ / = NCH _3, and

- (CH) -H 6; 3.14 and 3.3 / 2 mt, 1H none: -OCONHCH ₂ CH ₂ CH ₂ N = /; 4.01 (d, 1H, J = 7: --H3); 4.21 and 4.33 / 2d, 1H none, J = 9:

-CH2-20 ₎ ; 4.63 (s broad, 1H: --H2 '); 4.94 / d broad, 1H,

J = 10: -H 5]; 5.27 (broad d, 1H, J = 9.5: -H 3 '); 5.38 (dd, 1H, J = 11 and 7: --H 7); 5.44 / d, 1H, J = 9.5: --NHCOOC / _CH3 / ₃ /;

5.51 (s, 1H: --H 10); 5.68 (d, 1H, J = 7: -H 2); 6.09 (broad m, 1H) -NHCH ₂ CH ₂ CH ₂ N = /; 6.21 (broad t, 1H, J = 8.5: --H 13); 7.25 to

7.45 (mt, 5H: --C6 H5 3 '); 7.50 / t, 2H, J = 8: _{--OCOC6 H5} / H 3 and H // 5; 7.62 (t, 1H, J = 8: --COCO6 H5 / --H4 ₎ ; 8.10 (d, 2H, J = 8: -CO 2 C 6 H 5) -H 2 and -H 6 //.

To a solution of 5 mg of 3-tert-butoxycarbamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,10beta-dihydroxy-7beta - {[3- (4-Methylpiperazinyl) propyl] -1,8-carbamoyloxy} -9-oxo-11-taxen-13alpha-yl obtained above in 0.1 ml of 0.1 N hydrochloric acid solution is added, 3 ml of distilled water and lyophilized. 5 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,10beta-dihydroxy-7beta - {[beta] - {-] - 3- (4-Methylpiperazinyl) propyl / carbamoyloxy} -9-oxo-11-taxen-13a-phyl, having the following characteristics:

NMR spectrum / 400 MHz; D = 0 + Σ CDsCOOD /:

delta / ppm / 0.82 / s, 3H: _-CH3 16 or 17 /; 0.92 / s, 3H:

-CH ₃ 16 or 17 /; 1.1 / s, 9H: C / CH3 / 3 /; 1 4 to 1.8 / mt, 5H : -OCONHCH2CH2 CH 2 N =, -CH 2-14 and - (CH) -H 6; 1.48 / s, 3H: --CH3 19 /; 1.6 / s, 3H: --CH3 (18); 2 1 / s, COCHs / 2.28 / mt, 1H: - (CH) -H 6; 2.78 / s, 3H: -NCH3 / 3 /; 2.8 to 3.1 and 3.42 / mt and mf, respectively. 4H and 8H : -0CONHCH 2 CH 2 CH 2 N / CH2CH2 / 2 NCH 3 /; 3.57 / d, 1 H, J = 7: -H 3]; 4.01 and 4.1 / 2d, 1H each, J = 8 : -CH2-20 and -H 7 /; 4.3 to 4, 4 / -H 2 ': signal masked with solvent band; 4.73 / d, 1 H, J = 7: -H 3 '; 4.85 / d wide, 1H, J = 9: -H 5]; 5.02 / mt, 1H: -H 7; 5.24 / s, 1H: --H (10); 5.32 / d, 1H, J = 7 -H 2; 5.82 / t, 1H, J-9: -H 13 /; 7.02 / t, 1H, J = 8: -C6 H5 3 '/ H 4'; 7 12 / d, 2H, J = 9: - CeH 3 '- H 2 and -H 6 //; 7.22 m / z, 2H, J = 8 : -C 6 H 3 '- H 3 and -H 5 //; 7 41 / t, 2H, J = 8 -CO 3 C 6 H 5 / -H 3 and -H 5 //; 7.52 / t , 1 H, J = 8 -0C0CeH _p / 4 // H; 7.8 (d, 2H, J = 8): -CO 2 C 5 H 5 / -H 2 and -H 6 //.

Example 4

In analogy to Example 2, but using 6.95 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate - [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1- hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-1,3a-phayl and 0.88 ml of 3-morpholino-propylamine, after purification by high-performance liquid chromatography, using a mixture of methanol-1-isopropyl and 1-hexane / 20: 5: 7 5 v / v as the mobile phase, yields

1.53 g of 3-chloro-butoxycarbonylamino-2-hydroxy-3-phenyl-pionate / 2R, 3S / 4-acetoxy-2-alpha-benzoyloxy-5beta , 20-epoxy-1-hydroxy-10beta - [(3-morpholinopropyl) carbamoyloxy] -9-oxo-7beta- (2,2,2-trifluoroethoxy) carbonyloxy-11-taxen-13a-pha-yl in the form of white foam,

1.35 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta - / (3-morpholinopropyl) carbamoyloxy] -9-oxo-10beta- (2,2,2-trifluoroethoxy) carbonyloxy-11-taxen-13alpha-yl in the form of a white foam.

Compound 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2-alpha-benzoyloxy-5-beta, 20-epoxy-1-hydroxy-10beta - / (3- morpholinopropyl) carbamoyloxy / -9-oxo7beta- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl is converted to 3-tert-butoxycarbonylamino-2-hydroxy-3 by treatment with zinc in a mixture of methanol and acetic acid. (2R, 3S) 4-Acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta-dihydroxy-10beta - [(3-morpholinopropyl) carbamoyloxy] -9-oxo-11-taxen-13alpha-yl -feriylpropionate as described in Example 2 for 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) -4- and cetoxy-2a-4-benzoyloxy-5beta, 20-epoxy-1 hydroxy-10beta - [(3-dimethylaminopropyl) carbamoyloxy] -9-oxo-7beta- (2,2,2-trifluoroethoxy) carbonyloxy-11-taxen-13alpha-yl.

The product obtained has the following characteristics: NMR / 400 MHz spectrum; CDCl /:

delta / ppm / 1.15 / s, 3H: _-CH3 15 or 17 /; 1.28 / s, 3H:

-CH ₃ 16 or 17); 1.35 (s, 9H: --C (CH3 _{) 3} ); 1.68 / s, 3H: _-CH3 19 /; 1.65 to 1.9 / ml, 2H, -OCONHCH ₂ CH ₂ CH ₂ N = /; 1.88 / s, 3H: _-CH3 18 /; 1.9 (mt, 1H: - (CH) - H 6); 2.28 (mt, 2H: --CH2 - 14); 2.4 (s, 3H: --COCH3 ₎ ; 2.45 to 2.75 / mt, 7H: _CH2 N / CH ₂ CH ₂ / O ₂ and - / CH / - H 6 /; 3.28 and 3.42 / 2 mt, 1H each: -OCONHCH ₂ CH ₂ CH ₂ N = /; 3.8 / mt, 5H, _CH2 N / CH ₂ CH ₂ / H ₂ 0 and 3 /;

4.18 and 4.31 / 2d, 1H each, J = 8.5: _CH2 -20 /; 4.44 / dd, 1H,

J = 11 and 7 : -H 7 /; 4.63 / s broad, 1H: -H 2 '); 4.98 / d wide, 1H, J = 10 : -H 5 /; 5.27 / d broad, 1H, J = 9: -H 3 '; 5.41 / D 1 H, J = 9: --NHCOOC / _CH3 / ₃ /; 5.67 / d, 1H, J = 7; -H 2; 6.21 /with , 1H: --H 10 /; 6.25 / mt, 1H : --H 13; 6.58 / t wide, 1 H, J = 5

: -NHCH2CH2CH2N = /; 7.25 up to 7.45 cm -1, 5H: -C6 H 5 3 /; 7.52 / t, 2H, J = 8: -OCOC6H5 / -H 3 and -H 5 //; 7.25 to 7, 45 / mt, 5H -CeH 3 '; 7.52 / t, 2H, J = 3: -OCOC6H5 / -H3 and -H // 5; 7.62 m / z, 1H, J = 8: -OCOC3H5 (-H 4); 8.12 / d, 2H, Jz8 : -OCOCeHs (-H 2 and -H 6).

Compound 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta - [(3-morpholinopropyl) carbamoyloxy] - 9-oxo-10-beta- (2,2,2-trifluoroethoxy) carbonyloxy-11-taxen-13alpha-yl is converted in 3-tert-butoxycarbonylamino-2-hydroxy- 3-Phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5'beta, 20-epoxy-1, 10betadihydroxy-7beta - [(3-morpholinopropyl) carbamoyloxy] -9-oxo-11-taxen-13aa fa - zinc by treatment with zinc in a mixture of methanol and acetic acid as described in Example 2 for 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-10.beta. - / (3-dimethylaminopropyl) carbamoyloxy / 9-oxo-7.beta / 2,2,2-trichloroethoxycarbonyl / carbonyloxy-11-taxen-13.alpha.-yl.

The product obtained has the following characteristics: NMR spectrum / 400 MHz; CDCl /: .delta. (ppm): 1.11 (s) , 3H: -CH ₃ 16 or 17); 1, 24ps, 3H: -CH ₃ 16 or 17); 1.37 (s, 9H: -C (CH3) 3); 1, 6 to 1.9 / mt, 2H -OCONHCH = CHoCH = N = /; 1 81 (s, 3H-CH ₃ 19); 1, 9 3 / s, 3 H: -CH ₃ 18; 1.93 / mt, 1H : - (CH) -H 6]; 2.3 / d, 2H, J 8: _-CH2 - 14 /; 2.4 / S, 3H: --COCH 3 /; 2.4-2.7 / mt, 7H: --CH N / CHzCHc / - = O and - (CH) -H 6); 3,12 a 3.31 / 2 mt, 1H each: -OCONHCH ₂ CH _{2 S} CH = N /;

3.5 (broad m, 1H: --OH 2 '); 3,8 / mf, 4H: _CH2 N / CH-CH-0 /; 4.0 (d, 1H J = 7: --H3); 4.2 and 4.33 (2d, 1H each, J = 8.5: --CH = - 20); 4.64 (broad m, 1H: --H2 '); 4.94 (d, broad, 1H, J = 9.5: --H 5); 5.28 (broad d, 1H, J = 9: -H 3 '); 5.38 / dd _; 1H, J = 10 and 7: -H 7]; 5.45 / d br, 1 H, J = 9: --NHCOOC / _CH3 / ₃ /; 5.51 (s, 1H: --H 10); 5.68 (d, 1H, J = 7: -H 2); 5.8 (t, 1H, J = 5: -NHCH2CH2CH3N3); 6.21 (t, 1H, J = 8: -H 13); 7.25 to 7.45 / mt, 5H: C _E H S 3 '/; 7.51 / t, 2H, J = 8: -OCOC _E H S / H and 3 H // 5; 7.62 (t, 1H, J = 8: --COCO (C6H5) --H4); 8.12 (d, 2H, J = S: --COCO (C6H5) --H and --HQ).

1

Example 5 under reduced pressure (2.7 kPa) of the fraction (0.12 to 0.15) of the eluent of the fraction

To a solution of 0.29 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10-beta-bis- (2,2,2-tri-chloroethoxy) -carbonyloxy-11 -taxen-13alpha-yl 100 ml of acetone is added, under argon atmosphere, 0.31 ml of 3-methylaminopropyl amine is added. í nu. The reaction mixture is heated with stirring at about 60 ° C for 3 hours, cooled to about 20 ° C and evaporated to dryness at 40 ° C. 0.32 g of white pe is obtained, purified by chromatography on 30 mm / column. methylene or id-methanol, 95 in 10 ml portions. Fractions 7 to 15 are combined and evaporated to dryness under reduced pressure (2.7 KPa) at a temperature of about 40 ° C. 0.12 g of 3-tert-butoxycarbonyl-amide-2-hydroxy-3-phenylpropionate (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta is obtained, 10beta-bis - [(3-dimethylaminopropyl) carbamoyl] alumina having a size of 1.5 cm 5 vol. And odobeoxy / -9-oxo-11-taxen-13alpha-yl having the following characteristics:

in the form of a white foam having an optical rotation: [alpha] D ^{= [} alpha] = -26 [deg.] / c = 0.75; methanol /; NMR spectrum / 400 MHz; CDC1 ₃ /:

delta / ppm / 1.17 / s, 3H: _-CH3 16 or 17 /; 1.20 / s, 3H:

-CH ₃ 16 or 17); 1.36 / s, 9 H: : C / CH3 / 3 /; 1,6 to 1, 8 / mt, 4H : -NHCH2CH2 2 N / CH 3/2 /; 1.78 / s, , 3H: -CH ₃ 19 /; 1, 83 / Mt, 1H: - (CH) -H 6; 1, 96 / s, 3H : -CH ₃ 13 /; 2 , 25 (S, 6H) N / CH 3 / = /; 2.36 / s, 3H : -COCH3; 2 , 2 to 2. , 6 / mt, 6H : -CH2- 1 4 and -CH 2N / - CH3 / 2 /; 2 66 / mt 1H: - / CH / H 6 /; 3 24 / mt, 4 H NHCH2 CHS 2 N / CH3 / 2 / ; 3.92 / d, 1 H , J = 7: -H 3; 4.16 and 4.3 / 2d, 1 H kaž-

d, J = 8: -CH2-20 ₎ ; 4.62 (s broad, 1H: --H2 '); 4.93 (d, 1H, J = 9: --H 5); 5.27 / mt, 1H: --H3 '; 5.4 (mt, 1H: --H 7); 5.48 and 5.76 (2 mt, 1H each: -NHCH 2 CH 2 CH 2 N (CH 3) 2); 5,55 / d wide,

1H: NHCOOC (CH3); 5.64 (d, 1H, J = 7: -H 2); 6,16 / t wide,

1H, J = 9: -H 13]; 6.32 / s, 1H: --H 10; 7.3 to 7.5 (mt, 5H: 'C6H5'); 7.5 / t, 2H, J = 7.5: -OCOCeH ₅ / H 3 and H // 5; 7.51 (t, 1H, J = 7.5: --OCOC6 H5 / --H4 ₎ ; 3.1 (d, 2H, J = 7.5: --OCOC6 H5) - .delta.

To a solution of 10.6 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta -bis - [(3-dimethylaminopropyl) carbamoyloxy] -9-oxo-11-taxen-13alpha-yl obtained above in 0.2 ml of 0.1 N hydrochloric acid solution is added 0.4 ml of distilled water and the resulting solution is lyophilized. There was thus obtained 10 mg of 3-1e-tert-butoxycarbonyl-amino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, -2Q- epoxy-1-hydroxy-7beta, 10beta-bis - [(3-dimethylaminopropyl) carbamoyloxy] -9-oxo-11-taxen-13alpha-y, having the following characteristics:

NMR spectrum / 400 MHz; D2O / CH3COOD, 90: 10 v / v:

delta / ppm / 0.35 / s, 3H: _-CH3 16 or 17 /; 0.9 / s, 3H:

-CH 3 16 or 17); 1.10 / bs, 9H : - C / CH / 3 /; 1.5 / s, 3H: --CH3 19 /; 1.6 to 1.8 / m, 10H, CH ₃ 18 NHCH 2CH2 2 N / CH 3 (3), -CHc- 14, - (CH) -H 6]; 2.10 / s, 3H; -COCH 3 /; 2.3 / m, 1H: - / CH / -H 6 /; 2.65 / 2 s, 6H each: N / CH ₃ Λ /; 2.8 to 3 , 1 / vbm 8H: --CH2 N / _CH3 / 2, -NHCH ₂ CH ₂ CH ₂ N / _CH3 / ₂ /; 3, 6 / bd, 1H: -H 3; 4 and 4.15 / 2d, AB, 2H: _--CH2 - 20 /; 4.40 / bd, 1 H: -H2 ' /; 4.70 / vbs, 1H: -H 3 '; 4.90 (bd, 1H: --H 5); 5 10 / b d d 1H: --H 7 /; 5.35 (bd, 1H: --H2 '); 4.70 / vbs, 1 H H3 '; 4.90 / bd, 1 H : Ή 5 /; 5.10 (bdd, 1H: --H 7); 5.35 / b d, 1H: -H 2 /; 5.8 / t, 1H: -H 13; 6.05 / s, 1H: -H1 Q; 7.0 to 7, 25 / m t., 5 H: - (C 5 H 5); 7.4 / t, 2H, J = 7.5: _--OCOC6 H _S / H 3 and -H // 5; 7,5 / t, 1H, J = 7.5 : _{--OCOC6 H5} / H 4 //; 7.80 / d, 2H, J = 7.5 : -OCOC e H s / - H 2 a H δ //. Example 6 Analogous to the procedure Example 5 but with use i m

1.18 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, -20epoxy-1-hydroxy-9 oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl and 1.6 g of 3- (4-methylpiperazino) -propylamine gave 1.1 g of 3- 1-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-123-propionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta-bis - {[3] - (4-Methylpiperazinyl) -propyl / carbamoyloxy} -9-oxo-11-taxen-13a-f-yl in the form of a white foam having the following characteristics:

optical rotation: [alpha] D <^2> = -22.9 [deg.] / c = 0.51; methanol /; NMR spectrum / 400 MHz; CDCl /:

.delta. (ppm): 1.24 (s, 3H-CH ₃ 16 or 17); 1.4 / s, 9H: -0C0NHCH ₂ CH 2 CH ₂ N = /; 1.83 / s, 3H: --CH

J = 15, 11 and 2: - (CH) -H 6]; 2.01 / s, 3H / mt, 31H

CH 2 N / CH 2 CH 2 / 2NCH 3 - COCH

-CH ₃ 16 or 17); 1.28 / s, 3H

C / CH / and /; 1.6 to 1.35 (mt 19); 1.87 / ddd,

-CH 3 18; 2.3 to: - (CH) -H 6); m / z, 1H, J = 7

3.15 and 3.45 (mt -H 3); 4.21 and 4.4H 1H, 2.7 and -CH2-14; 2.7 (mt, 1H 4H) -OCONHCH2CH2CH = N = /; 4.0 32 (2d, 1H each, J = 3: -CH220); 4.66 (d, 1H, J = 2: -H 2 '); 4.93 / d broad, 1H, J = 9: -H

5 /; 5.28 / ml, 1 H / _CH3 / ₃ /; 5.7 / d,

-H 3 '; 5.4 to 5.5 (mt, 2H: -H7 and -NHCOOClH, J = 7: -H2); 6.0 and 6.4 / 2 mf, 1H each: _{CH2 NHCH2} CH2 N = /; 6.21 / t, 1H, J-9

-H 10; 7.3-7.5 (mt, 5H: -C6 H5 O-COC6 H5) -H 3 and -H 5 //; 7.64: -H 13]; 6.4 / s, 1 H:

/; 7.5 l / t, 2H, J = 7.5:

/ t, 1H, J = 7, 5: _--OCOC6 H S / H // 4;

8.12 (d, 2H, J = 7.5: --OCOC6 H5) --H2 and --H6].

A solution of 0.35 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta, -bis- The {[3- (4-methylpiperazinyl) propyl] carbamoyloxy} -9-oxo-11-taxen-13alpha-yl obtained above in 12 ml of 0.1 N hydrochloric acid is lyophilized. 0.365 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta-bis- {[3- (4-Methylpiperazinyl) -propyl] carbamoyloxy} -9-oxo-11-taxen-13alpha-yl having the following characteristics:

optical rotation: [alpha] D <^2> = -22 [deg.] / c = 0.41; methanol /;

NMR spectrum / 400 MHz; D 2 O /:

.delta. (ppm): 1.1 (s, 3H) : - CH ₃ 16 or 17 /; 1, 14 / s, 3H -CH ₃ 16 or 17); 1.36 /with , 9H: -C (CH3) / 3 /; 1.72 and 1.92 / 2 p 3H each: CH ₃ 18 a CH3 19 /; 1.65 until 2.05 / mt, 7H -0C0NHCH2CH2CH2N =, - CH2- 1 4 and - (C H) -H 6 /; 2, 38 /with , 3H

-COCH 3 /; 2.55 / mt, 1 H -CH (-H 6); 2, 92 and 2.94 / 2.6H -nch ₃ /; 3 , 0 to 3.7 / m t 24H: -OCONHCH 2CH2C H ·.? N / CH 2 CH 2/2 NC H 3 /; 3.79 / D 1H, J = 7: -H 3 /; 4.23 and 4.4 / 2d, 1H each, J = 9 -CH ₃ - 20 / ; 4.6 7 / d, 1H, J = 7: -H 3]; 4. 23 a 4.4 / 2 d. 1H each, J = 9: -CH = - 20 /; 4.67 / d, 1 H J = 7: -H 2 '/; 4.98 / m f 1H: -H 3 '; 5 , 16 / 0 broad, 1H, J = 9 : -H 5 /; 5, 33 / O, 1H, J = 11 and 7: -H 7 /; 5.58 / d, 1H, J = 7 : -H 2 /; 6, 07 / t, 1H = 9: -H 13; 6. 2 8 / sec , 1H: -H 10; 7, 2 7

(t, 1H, J = 7.5: -C6 H5 3 ') -H 4 H; 7.38 / d, 2H, J = 7.5: -C6 H5

3 '/ -H 2 and -H // 6; 7.48 / t, 2H, J = 7.5: -C 6 H 3 '- H 3 a -H 5 //; 7.67 / t, 2H, , J -7.5: -OCOCeOH / H 3 and -H // 5; 7.48 / t, 2H, J = 7.5: - C e H 5 3 '/ -H 3 a -H // 5; 7 67 / t, 2H, J = 7. , 5: -OCOCeHs / - H 3 a -H 5 //; 7.78 / t, 1 H, J = 7 , 5: -OCOCeOH / H 4 //; 8.18 / d, 2H , J = 7.5: -OCOC6 hs / -H 2 and - H ô //.

Example 7

By analogy to Example 5, but using 0.58 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- [2R, 3S] 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1- hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-1 -richloroethoxy) carbonyloxy-11-1-axen-13alpha-yl and 0.73 ml of 3-morpholinopropylamine gave 0.4 g of 3-tert-butoxycarbonylamino-2 -hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta-bis - [(3-morpholinopropyl) carbamoyloxy] -9-oxo- 11-taxen-13alpha-yl in the form of a white foam having the following characteristics: optical rotation: [α] D ² ° - -24.7 ° / c = 0.52; methanol /; NMR spectrum / 400 MHz; CDCl /:

delta / ppm / 1.25 / s, 3H: _-CH3 15 or 17 /; 1.28 / s, 3H:

-CH ₃ 16 or 17); 1.41 (s, 9H: --C (CH3 _{) 3} ); 1.5 to 1.85 / mt,

4H; -OCOHCH ₃ CHc CH-N = /; 1.31 / s, 3H: _-CH3 19 /; 1,89 / ddd

1H, J = 15, 11 and 2: - (CH) -H 5]; 2.0 / s, 3H: _-CH3 18 /; 2.36 / mt, 2H: CH _2-14 /; 2.35 (s, 3H: --COCH3 ₎ ; 2.4 to 2.6 / ml, 12 H - CH 2 N / CH ₂ / O 2; 2.7 (mt, 1H) - (CH) -H 6]; 3.15 to 3.45 / mt, 4H: -OCONHCH -CH-CH ₃ N = /; 3.76 (mt, 8H): --CH.dbd.N (CH.dbd.CH2 / ₂ O);

3.98 / d, 1H, J = 7: -H 3; 4 , 20 and 4.31 / 2d , 1H each, J = 8: -CH = -20 /; 4.65 (d, 1H, J = 2): -H 2 '/; 4 98 1 / d broad, 1H J = 10 : -H 5; 5.3 / L, 1H, J = 9 : -H 3 '/; 5.4 / d, 1H, J = 9: --NHCOOC / _CH3 / ₃ /; 5.45 / mt, 1H : -H 7 /; 5 7 / d , 1H, J = 7: -H 2]; 5.6 to 5.2 / mf , 2H: -NHCH2CH2CH ₂ N = /; 6, 22 m / z, 1H, J = 9: -H 13 /; 6.38 / s, 1H: --H (10); 7, 3 to 7.5 / m t 5H: —CeH5 3 '; 7.51 / t, 2H, J = 7.5: --OCOC e H 5 / -H 3 a -H // 5; 7.62 / t, 1 H, J = 7.5: -OCOC6 H5 / -H4 /; 8 1 1 / d, 2H J = 7 5: -OCOCeOH / -H 2 and -H 6 //. To the solution 11.5 mg of 3-tert .-Butoxycarbonylamino-2-hydroxy-

3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta-bis - [(3-morpholinopropyl) carbamoyl oxy] -9-oxo-11- of taxen-13a-1-yl, obtained above, in 0.2 ml of a 0.1 N hydrochloric acid solution, 0.4 ml of distilled water is added and the solution obtained is lyophilized. 12 mg of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate- (2R, 3S) 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta-bis- ((3-Morpholinopropyl) carbamoyloxy) -9-oxo-11-taxen-13a-phyl, having the following characteristics:

NMR spectrum / 400 MHz; D = O (CH ₃ COOD, 90: 10 v / v): delta (ppm): 0.85 (s, 3H: -CH ₃ 16 or 17); 0.9 (s -CH 2 16 or 17); 1.1 (b, 9H: --C (CH3 _{) 3} ); 1.5 / s,

3H C H 3

3H

19 /; 1.6 to 1.8 / m, 10 H:

14, - (CH) -H 6]; 2.1 (s, 3H); 2.8-3.10 [mu] m, 12H

-CH ₃ 18, -OCONHCH ₃ CH = CH = N =, —CH ₃ -: -COCH ₃ -; 2.3 (m, 1H: - (CH) - H: - CHaN (CHaCH3)); 3.3 / bm, 4H:

-OCONHCH ₃ CH ₃ CH with N = /; 3.6 / m, 4H

-CH and N (CH 2 CH 2); 3,85 / bm,

4H

-CHsN / CHsCHs / group /; 4 and 4.15 (bd, AB, 2H: --CH2 - 20); 4.4 (bd, 1H: --H2 '); 4.75 (bs, 1H: --H 3 '); 4.9 / bd, 1H: --H 5 / 5.1 / bdd, 1H; -H 7; 5.35 (bd, 1H: --H2); 5.8 / bt, 1H

-H 13; 6.04 / s, 1H

7.4 / t, 2H, J = 7.5:

J = 7.5: _--OCOC6 H _S / H and H // 6.

-H 10; 7.0 to 7.25 (m, 5H: -CeHe 3 ')

-OCOCeH5 / -H3 and -H5 /; 7.52 / t, 1 H,

4 //; 7.8 (d, 2H, J = 7.5): --COCO (C6H5) --H2

The novel compounds of the formula Ia show interesting biological effects.

The novel compounds of formula (Ia) exhibit specific activity in abnormal cell proliferation and possess therapeutic properties which enable the treatment of diseases with pathological conditions which are associated with abnormal cell profiling. Pathological conditions include abnormal proliferation of malignant or normal cells in various tissues and / or organs, including muscle, bone or connective tissue, skin, brain, lung, genital organs, lymphatic system, kidney, breast or blood cells, liver, digestive tract , pancreas, thyroid, or adrenal gland. These pathological conditions may also include psoriasis, solid tumors, ovarian, uterine, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, choiangiocarcinoma, choirococcus, neurobastoma, Wilms' tumor, Hodgkin's disease. multiple myelomas, chronic lymphocytic leukemia, acute or chronic granulocytic lymphomas. The novel compounds of the invention are particularly useful in the treatment of ovarian cancer. The compounds of the invention are useful for preventing or retarding the manifestation or restoring pathological conditions or for treating them.

The compounds of the invention may be administered to patients in a variety of forms adapted to the route of administration chosen, preferably parenterally. This route of administration includes intravenous, intraperitoneal, intramuscular or subcutaneous. Most preferred is the application of intraperitoneal to or intravenous.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula Ia in an amount sufficient to be used in human or veterinary therapy. The compositions may be prepared by conventional methods using one or more pharmaceutically acceptable excipients, carriers, or excipients. Conventional carriers include diluents, sterile aqueous media, and various non-toxic solvents. Preferably, the compositions are available

7 in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifiers, colorants, preservatives or stabilizers.

The choice of excipients or excipients depends on the permeability and chemical properties of the compound, the intended route of administration and good pharmaceutical experience.

For parenteral administration, sterile aqueous or non-aqueous solutions are used. Natural vegetable oils, for example olive oil, sesame oil or paraffin or injectable organic esters such as ethyl oleate, may be used to prepare a solution of anhydrous or aqueous suspensions. Sterile aqueous solutions may consist of solutions of pharmaceutically acceptable salts in water. Aqueous solutions are suitable for intravenous administration when the pH is suitably adjusted and isotonicity is ensured, for example, with sufficient sodium chloride or glucose. Sterilization may be accomplished by heating or by any other means which does not alter the composition.

It goes without saying that all products as part of the compositions of the invention must be pure and non-toxic in the amounts used.

The compositions should contain at least 0.01% of the therapeutically active agent. The amount of active ingredient in the composition is such. what could be prescribed with the usual put in fittings. Suitably, the compositions are prepared so that a unit dose contains from about 0.01 to 1000 mg of active ingredient when administered parenterally.

The treatment intervention may be carried out at the same time as other treatment interventions, including anti-neoplastic drugs, monoclonal antibodies, immunological preparations or radiotherapy, or biological response modifiers. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (alpha, beta or delta) and TNF. Other chemotherapeutic agents useful in the treatment of disorders caused by abnormal cell proliferation include: but not limited to, alkylating agents such as nitrogen mustards, mechlorethamine, cyclophosphamide, melphalan and chlorambuci 1, and 1-sulfonates such as busulfan, nitrosoureas such as carmustine, lomuzine, semustine and streptozocin, triazines such as decarbazine antimetabolites, for example folic acid analogs such as methotrexate, pyrimidine analogs such as fluoruracil and cytarabine, purine analogs such as mercaptopurine and thioguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendezin, epipodophyllotoxins, such as etoposidylotoxins, such as etopososidicides such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes , such as L-asparaginase, various other substances such as platinum complex compounds such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid inhibitors such as mitotane and aminoglutethimide, hormones and antagonists such as adrenocort icosteroids, e.g. prednisone, progestagens such as hydroxyprogesterone caproate, methoxyprogesterone acetate, and megestrol acetate, estrogens such as diethyl 1 bestro 1 and ethinyl estradiol 1, antiestrogens such as tamoxifen, androgens such as testosterone propionate and 1-oxymesterone.

The dosages used to carry out the methods of the invention are those that permit the administration of a prophylactic or maximal therapeutic response. Dosages vary depending on the route of administration, the product selected and the characteristics of the subject being treated. Generally, dosages are therapeutically effective in the treatment of disorders caused by abnormal cell filtration. The active compounds according to the invention can be administered as necessary in order to obtain the desired therapeutic effect. Some diseases may respond quickly to high or low doses, then low maintenance doses should be taken care of or discontinued. Generally, low doses are administered at the start of treatment and, if necessary, increasing doses are administered until the optimum effect is achieved. For other diseases, it may be beneficial to administer dosages one to eight times a day, preferably 1 to 4 times a day, depending on the physiological needs of the particular disease. It is also possible to administer ib and one, at most two doses per day to some patients.

dosages ranging from 0.5 L to 10 mg / kg are contemplated. on benefits

In humans, doses ranging from 0.01 to 200 mg / kg are usually envisaged. For intraperitoneal administration, a range of from 0.1 to 100 mg / kg, preferably up to 50 mg / kg, most preferably in the range of 0.1 to 50 mg / kg is usually considered. preferably in the range of 0.1 to 5 mg / kg, most preferably in the range of 1 to 2 mg / kg. Of course, when choosing the most appropriate dosage, it is necessary to take into account the route of administration, the weight of the patient, his general health, age, and any factors that could affect the effectiveness of the treatment.

The following example illustrates one composition of the invention.

Example

40 mg of the product obtained in Example 1 are dissolved in 1 ml of Emulpor EL 620 and 1 ml of ethanol, and the solution is then diluted by adding 18 ml of physiological serum.

The composition is administered as an infusion with saline over 1 hour.

Industrial usability

The novel taxol analog derivatives of the invention have shown useful efficacy in the treatment of various neoplasms, alone or in combination with other active ingredients and in a suitable dosage form.

Claims (5)

PATENT Claims in which: Ar aryl, R is a group of formula II RtO- (11) in which R? represents a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 8 carbon atoms δ carbon atoms or a bicycloalkyl group containing 7 to 10 carbon atoms, which groups may optionally be substituted by one or more substituents selected from halogen atoms and hydroxyl groups, C 1 -C 4 alkyloxy groups, dialkylamino groups, each alkyl group the moiety contains 1-4 carbon atoms, piperidine, morpholine or 1-piperazine residues optionally substituted at the 4-position with an alkyl group containing 1-4 carbon atoms or a phenylalkyl group having 1-4 carbon atoms in the alkyl moiety, and cycloalkyl 3 1 groups having 3 to 6 carbon atoms, cycloalkenyl groups having 4 to 6 carbon atoms, phenyl groups, cyano groups, carboxyl or alkyloxycarbonyl groups in which the alkyl component contains 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or a plurality of atoms or groups selected from halogen atoms and alkyl groups containing 1 to 4 carbon atoms or alkoxy groups containing 1 to 4 carbon atoms, o or a saturated or unsaturated nitrogen containing heterocycle containing 4 or 6 members and optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms, it being understood that cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups groups containing 1 to 4 carbon atoms, the substituents R 1 and R a, identical or different, represent a hydrogen atom or a group of formula III NCO (ΙΠ) in which the substituents R ₃ and R 3, the same or different, denote a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms, which is optionally substituted: a) a hydroxyl, carboxyl, and alkyloxycarbonyl group, the alkyl component of which contains 1 to 4 carbon atoms and which is optionally substituted by a phenyl group, b) a group of the formula IV N / IV / Re wherein each of R and R, identical or different, · a hydrogen atom or an alkyl group, straight or branched chain of 1 to 4 carbon atoms, and the substituents _R and R, connected together, form with the nitrogen atom to which ' are bound, saturated or unsaturated, five- or six-membered heterocycle optionally containing a second heteroatom selected from nitrogen atoms optionally substituted by an alkyl group containing 1 to 4 carbon atoms, or a benzyl group, oxygen or sulfur, or R ₃ substituents and R 4, taken together, form with the nitrogen atom to which they are attached, saturated or unsaturated, a five- or six-membered heterocycle optionally containing a second heteroatom selected from nitrogen atoms optionally substituted with an alkyl group containing 1 to 4 atoms carbon or benzyl group, oxygen or sulfur, it being understood that at least one of the subst R 1 or R _c is a group of the formula (III) and also, if any, their acid addition salts. 2. A process for the preparation of novel derivatives according to claim 1, characterized in that the amine of formula V is treated. Rs = NH (V) R. X in which R 5 and R 6 are as defined in claim 1, to a taxane derivative of the general formula VI wherein: I: R and Ar are as defined in formula (VII) in claim 1 to form (VII). wherein R and Ar are as defined above, G 1 and G; represents each group of formula II or a protecting group CCl3CH2OCO-, it being understood that at least one of the substituents G1 and G; represents a group of formula (II), followed, if desired, by the replacement of one or more of the protecting groups CCl3CH2OCO- by a hydrogen atom, separation of the products of formula (I) from their mixture and isolation of the obtained product optionally in salt form. 3. A process according to claim 1, wherein the amine of formula I is treated with a taxane derivative of formula III in a non-reactive organic solvent such as a halogenated aliphatic hydrocarbon, e.g. m ethylene chloride, at a temperature ranging from 0 ° C to the boiling point of the reaction mixture. 4. A process according to claim 3 wherein the replacement of the 2,2,2-trifluoromethoxycarbonyl protecting group with a hydrogen atom is performed by treatment with zinc in acetic acid, optionally in the presence of methanol, at a temperature ranging from 30 to 80 ° C. A pharmaceutical composition comprising a sufficient amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable non-reactive or pharmacologically active diluents or excipients.