NL8204711A - N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THERAPEUTIC USE. - Google Patents

Description

Wf '·:' ............ ^ N / 31.242-Kp / Pf / vdM -> '* - 1 - N- (Vinblastinoyl-23) derivatives of amino acids, their preparation and therapeutic application .

The present invention relates to new bisindole alkaloids. More particularly, the invention relates to amino acid combination products with derivatives of vinblastine, to a process for their preparation, their use as anti-tumor agents and to pharmaceutical compositions containing them.

These new derivatives of vinblastine can be used in the treatment of leukemia and malignancies in humans.

Vinblastine-type bisindole alkaloids are known carbon skeletal compounds of the general formula 1 of the formula sheet.

As examples of these compounds can be cited: vincaleukoblastin (US patent 3,097,137), leurocristine or vincristine and leurosidine (US patent 3,205,220), finger lycinate (Belgian patent 659,112) and vindesine (Belgian patent 813,168).

The latter compound is obtained by chemical modification of natural vinblastine (1, R 2 = OCH 2, R 2 = COCH 3), which can be obtained by extraction of the leaves of Catharanthus roseus.

Vinblastine, vincristine and vindesine are commercially available for use in human therapy, more particularly for the treatment of leukemia and some solid tumors.

However, it has been found that these drugs have adverse side effects. Vincristine exhibits neuro-toxic effects and vinblastine has a high toxicity to so far concerning erythropoietic tissues.

Their mechanism of action is similar to the one postulated for the anti-mitotic action of colchicine. These drugs are said to act by inhibiting the polymerization of tubulin, yielding microtubu-buli and consequently inhibiting cell division in the meta-8204711% -2 phase.

The use of 1: 1 complexes of anti-tumor tubilin / bisindole alkaloids is described in Belgian patent 854,053.

In some cases, lower toxicity and more efficient chemotherapeutic activity were observed than for the corresponding free alkaloids.

Other chemical modifications of vinblastine have been tested. Similarly, finglycinate sulfate (1, sulfate, 10 = 0CH3, R2 COCH2N (CH3) 2 - Cancer Research 1967, 27, 221-227) has been tested in clinical trials, but generally does not appear to be better than vinblastine or vincristine .

Belgian patent 813,168 describes Vindesine (1, R 2 = NH 2, R 2 = H) and other vinblastine-C3-car-15-bonamide derivatives. Later reports confirmed the therapeutic importance of vindesine or 3-carbonamide-4-0-deacetylvinblastine, but this compound was found to be inactive for the treatment of murine 1210 leukemia grafted in mice (see CJ Barnett et al., J. Med. Chem. 2, 88, 20, 1978).

The new compounds described in the present application can significantly delay the death of mice grafted intravenously with P 388 and L 1210 leukemias.

25 Activities relative to experimental P

Surprisingly, 388 tumors proved far superior to the Vinca alkaloids compared to them. Total remission has been observed in numerous cases.

The compounds of the invention further exhibit other important and unexpected advantages compared to vinblastine and known analogues, in particular vindesine.

More specifically, the observed toxicity is generally lower than the corresponding toxicity of vindesine or vincristine.

More specifically, the novel compounds of the present invention are those of the general formula II of the formula sheet wherein R is an α-amino acid ester, 8204711 »- 3 - (? -: .......... .................

which if necessary. is protected and bonded to the vinblastin-23-oyl radical by an amide bond, wherein the straight or branched ester group contains from 2 to 9 carbon atoms and R 1, is a hydrogen atom or a hydroxy group, R 2 is a hydrogen atom, a formyl-5 group or a C 2 -C 8 acyl group, Rg is a hydrogen atom or a methyl group or a formyl group, with the proviso that compounds wherein Rg is methyl and R 1 is a β-hydroxy group are excluded; or their acid addition salts with mineral or organic acids.

Particular preference is given to compounds of the formula III of the formula sheet, in which R 1 is a hydroxy group or a hydrogen atom, R 2 is a hydrogen atom, a formyl group or a C 2 -C 6 acyl group, R g is independently viewed, a hydrogen atom, straight or branched C 1 -C 8-15 alkyl, hydroxy-C 1 -C 8 alkyl, aminohydroxy-C 1 -C 8 alkyl, carbon-xy-C 2 -C 8 alkyl, amido-C 8 -C 8 alkyl, guanadino-Cg- C 4 alkyl, amino C 1 -C 6 alkyl, thiol C 1 -C 6 alkyl, cysteinylmethyl, methylthioethyl, benzyl, hydroxybenzyl, or a group of formula 4 or 5 of the formula sheet, or Rg together with the carbon, to which it is attached, and the nitrogen of the amido group forms an azole or a hydroxyazole ring; Rg is a hydrogen atom or a methyl group or a formyl group and Rg is a straight or branched C8 -C8 alkyl, or a benzyl group, provided that compounds in which Rg is simultaneously 3-25 OH and Rg -CHg are excluded and wherein -COOR 4 is preferably the carboethoxy or the carbomethoxy group? or their acid addition salts with a mineral or organic acid.

In a preferred embodiment, the structure

R O

ture portion, j3 jj -nh-ch-cor4 30 in the general formula 3, an ester derived from one of the naturally occurring amino acids and their optical isomers with D-configuration, namely glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, aspargine, glutamine, arginine, lysine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, proline, histidine, hydroxylysine or hydroxyproline.

The compounds can be referred to as 3-decarbomethoxy-0-4-deacetylvinblastine-3-carbonamide. She 8204711

* V

However, in the future, preference will preferably be designated as N- (vinblastin-23-oyl) or N- (vincristinoyl-1-23) derivatives of amino acids.

Particularly preferred compounds of the invention of general formula 2 are those wherein 1 * 2 is hydrogen and the amino acid residues are derived from one of the following amino acids: L- or D-tryptophan, leucine, isoleucine, valine, alanine or phenylalanine. Among these, L-tryptophan, L-isoleucine and L-alanine are of particular interest.

More particularly, the present invention describes reaction products of amino acids with vincristine, 0-4-deacetylvincristine, deformyl-O-4-deacetylvincristine and deoxyvinblastine-B.

The latter compound can be obtained by hydrogenation of anhydrovinblastine, which has been obtained by dehydration of vinblastine or by coupling vindoline to catharantine (Potier et al., JACS 98, 7017, (1976)).

The most preferred compound of the invention is the ethyl N- (O-4-deacetyl-4'-deoxyvinblastin-23-oyl) -tryptophanate.

When the amino acid contains functional groups in the side chain (formula 3), such as lysine or cysteine, it may be necessary to protect the functional groups by a known method.

Protection can be achieved, depending on the nature of the group to be protected, by condensing a benzyl, t-butyl, benzyloxycarbonyl, t-butoxy trifluoroacetylcarbonyl or trityl radical. Other known protecting groups in peptide chemistry can be used successfully.

The compounds of the present invention can be prepared in the usual manner from corresponding derivatives of vinblastine, by hydrazolysis, followed by nitrosation and reaction with the amino acid ester according to the reaction sequence I, as shown on the formula sheet.

The first step of the process is the addition of anhydrous hydrazine in excess of a solution of 8204711 rr; .......-- ....

- 5 - φ ψ blastine base in anhydrous methanol. The solution is heated under an inert atmosphere for 12 h to 12 d, at a temperature of about 30-70 ° C. Preferably, the temperature is kept at around 60 ° C.

The hydrazide of the bisindole derivative is isolated thereon by addition of water, extraction with dichloromethane and concentration. The compound can be purified later by preparative chromatography (neutral silica).

In the case of vincristine, the product obtained is 10 O-4-deacetyldeformylvincristine carbonhydrazide.

During the second stage, the hydrazide function of the modified vinblastine is converted into an acyl azide. This conversion is effected in a known manner by adding sodium nitrite to the hydrazide dissolved in a water / methanol / acid mixture.

The acid to be used can be hydrochloric acid.

The reaction temperature is kept between 0 and 5 ° C. After extraction with a water-immiscible aprotic solvent, preferably dichloromethane, the organic phase is partially concentrated.

The actual acyl azide is preferably not isolated, but added directly to the amino acid ester, or possibly. a protected derivative thereof, dissolved in dichloromethane.

The amount of amino acid to be used is about 1 to 5 equivalents of the modified vinblastincarbonazide.

The reaction mixture is kept between -3 and + 10 ° C for 8-72 h and generally for 15 h. The reaction can be easily monitored by means of thin layer chromatography. After concentration, the compound according to the invention of the formula II can be converted into a sulfate salt or another salt, derived from a mineral or organic acid, by crystallization from a methanolic solution of the corresponding acid.

The compounds of the invention can be purified by conventional techniques, such as chromatography or recrystallization.

8204 71 1

V V

- 6 -

If desired, the 4-0-deacetyl-vinblastine derivative thus obtained can be re-acylated, either directly to yield the vinblastine derivative 3, wherein R 3 is COCH 3 (J. Med. Chem. 22, 391, 1979), or by the foregoing. formation of the 3,4-diacetoxy derivative, followed by selective hydrolysis of the 3-acetoxy group in position 3. The hydroxy group in can be conventionally esterified with other activated acid derivatives containing 2-9 carbon atoms. The 0-4 formyl derivatives are obtained by formylation (formic anhydride) of the corresponding O-4-peacetyl compounds (see Belgian Patent 660,843).

The present invention also relates to the industrial and in particular pharmaceutical applications of the new bisindole alkaloids.

In particular, the compounds of the present invention exhibit very useful anti-tumor properties useful in human therapy.

These amino acid derivatives can be used to treat L 1210 or P 388 type leukemias, gliomas, lymphosarcomas and other leukemias or malignancies. In medicine they can be used to treat Hodgkin's disease and other solid tumors that can be treated with vinblastine, vin-cristine or vindesine. The present compounds are also useful in veterinary science for the treatment of tumors in animals.

Other interesting therapeutic applications can also be considered for the new derivatives of bis-30 indole alkaloids. It has been described that vinblastine can be used to treat some forms of joint inflammation (U.S. Patent 4,208,411) and that vincristine can be used to treat psoriasis (U.S. Patent 3,749,784).

In therapeutic application, the compounds of the invention, if necessary. in the lyophilized form, preferably administered parenterally, dissolved in a pharmaceutically acceptable solvent, in the form of a 8204 71 1 *. 0 '.........................., - 7 - base or of a pharmaceutically acceptable acid addition salt.

Among the acid addition salts are the non-toxic and pharmaceutically acceptable salts such as inorganic acid salts such as hydrochloric, phosphoric and sulfuric acid salts, or organic acid salts such as acetic, propionic, succinic, tartaric, oxalic, methanesulfonic and benzenesulfonic acid salts are preferred.

Physiological water and other saline solutions buffered, eg with a phosphate, are suitable solvents. In general, the compounds can be used in human therapy in a manner analogous to the art and with the limitations of using other Vinca type alkaloids.

The active agent is generally administered under a posology ranging from 0.01 mg to about 5 mg / kg depending on the derivative and the therapeutic scheme used. Total weekly doses will generally be between 0.1 and 35 mg / kg.

The compositions according to the invention are prepared in unit doses of 2-900 mg.

The compounds of the invention can be used alone or in combination with other carcino-static agents, including, for example, the alkylating agents, the anti-metabolites, such as methotrexate, 5-fluorouracil, 6-25 mercaptopurine, 6-thioguanine, the cystosine arabinosides and antibiotics, such as actinomycin D, daunorubicin, adriamycin and cis-dianinine dichloro platinum. In particular, the new vinblastine derivatives can be used in combination.

The following specific examples non-limitatively illustrate the method of obtaining the compounds of the invention.

EXAMPLE I

1. Preparation of O-4-deacetyl-N-deformylvincrinine monohydrazide-A.

985 mg of vincristine base was dissolved in a mixture of 10 ml of anhydrous hydrazine and 10 ml of methanol. The reaction mixture was kept at 60 ° C with stirring for 22 h. The reaction mixture was then treated with water and then 8204 71 1 - 8 - with water saturated with NaCl. The aqueous solution was extracted 8 times with 15 ml of dichloromethane. The combined organic phases were treated with 20 ml of water, then with 25 ml of water saturated with NaCl and finally dried over 5 Na 2 SO 4. After filtration and vacuum concentration, 900 mg of 0-4-deacetylvincristine monohydrazide (purity above 90%) were obtained.

NMR Spectrum (CDCl 3, 360 MHz) 9.76 (s, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.53 (d, 1H), 7.24 and 7.07 (m, 3H), 6.82 (s, 1H), 6.22 (s, 1), 5.87 (dd, 1h), 5.67 (d, 1H), 5.43 ( s, 1H), 4.03 (s, 1H), 3.94 (s, 3H), 3.86 (s, 1H), 3.73 (s, 3H), 3.52 (s, 3H), 2.82 (s, 2H), 2.51 (s, 1H), 0.93 (2t, 2 x 3H).

Mass spectrum (electronic ionization shock) 15 154, 294, 355, 413, 524, 555, 695, 710, 723, 736, 739, 755 (M + 1) - 768, 769, 782; calculated for ^ 42 ^ 54 ^ 6 ^ 7: 754.942.

2. Preparation of the acid azide of modified vincristine.

A solution of 850 mg of vincristine monohydraside-A in 20 ml of methanol was treated with 63 ml of 1N HCl and 175.5 mg of sodium nitrite for 15 min at 0 ° C.

The solution kept at 0 ° C was then neutralized with NaHCO 4 at 0 ° C and then extracted 3 times with dichloromethane. The combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo without heating until a solution of about 10 ml was obtained.

3. Reaction with ethyl tryptophanate.

300 mg of ethyl tryptophanate was then added with stirring at about 4 ° C and the reaction was monitored by tlc. After 10 days, the reaction product was purified by chromatographic separation (40 g silica gel 60, elution solvent ether / NH 4 saturated methanol 96: 4 vol / vol).

35 15 ml fractions were collected, which were checked by TLC. The unreacted amino acid was first collected (fraction 30 to 40). The eluent was changed (ether / NH 4 saturated methanol 86:14) and the 8204 71 1 - 9 - reacted derivatives were collected as three fractions: fractions 44-45: 30 mg; fractions 46-53: 257 mg; fractions 54-60: 115 mg).

The second part was ethyl N- (O-4-deacetyldeformylvincristin-5 23-oyl) tryptophanate, Ia, which was homogeneous by tlc.

Mass spectrum: 984, 970, 956 (M + + 1), 913, 912, 899 (DCI isobutane), calculated for C55Hg6Ngo9: 955.181. UV spectrum (CH-jOH): max: 282 (4.20) - 290 (4.18) - 322 (3.96 10 min: 254 - 287 - 305 IR spectrum: (cm "1) 3400 - 2920 - 1720 - 1660 - 1610 - 1485 - 1450 - 1370 - 1345 - 1330 - 1290 - 1220 - 1165 - 1130 - 1025 - 1005 - 920 - 885 - 830 - 740 15 NMR spectrum (CDCl ^) 360 MHz (ppm) 8 .50 (s, 1H), 8.03 (s / 2H), 7.77 (d, 1H), 7.60 (d, 1H), 7.57 (d, 1H), 6.95 (s, 1H), 6.35 (s, 1H), 5.89 (dd, 1H), 5.78 (d, 1H), 4.75 (q, 1H), 3.88 (s, 3H), 3, 67 (s, 3H), 1.23 (t, 3H), 0.98 (t, 3H), 0.89 (t, 3H).

Ethyl-N- (0-4-deacetylvincristine-23-oyl) triptophanate Ib.

The deformed derivative Ia (257 mg) was reformylated using the method of Belgian Patent 811,110.

The crude product thus obtained was purified by chromatographic separation using a 20 cm column (silica gel, 30 g) and successively 3 eluents: ether / NH 2 saturated methanol 92: 8; 88:12; 86:14. The effluent was collected in 15 ml fractions. Fractions 44-54 (34.1 mg) contain the N-atom reformed derivative Ib.

Mass spectrum (isobutane DCI): 1011, 997, 983 (M + + 1), 970, 982, 996, 998, 999, 1012

Calculated for C56Hg6N6 ° 10 = 9f * 3.192 35 UV spectrum (CH ^ OH) max: 270 (4.18) - 290 (4.11) plateau 280 (4.12) shoulder (4.03) IR spectrum ( KBr)

* ..ijimulilUI

8204711 - 10 - tires at 3400 - 3040 - 2960 - 2920 - 2880 -2850 - 1735 - 1725 - 1680 - 1670 - 1665 - 1610 - 1490 - 1450 -1225 - 745.

EXAMPLE II

Ethyl N- (0-4-deacetyldeoxy-4'-vinblastin-23-oyl-B) tryptophanate, lc.

The O-4-deacetyldeoxyvinblastine hydrazide was prepared according to the procedure described in U.S. Patent 4,203,898 (assigned to Ely Lilly Co., column 24, line 51 and following).

Then 500 mg of the hydrazide in 12 ml of methanol was treated for 15 min at 0 ° C with 37 ml of 1N HCl and 104 mg of NaNO2 »

The solution was then neutralized with 15 NaHCO 2 and extracted six times with 15 ml of dichloromethane. The organic phases were dried over Na2SO4 and concentrated to a volume of about 10 ml.

The dissolved azide was then contacted with ethyl tryptophanate (300 mg) with stirring at 4 ° C.

The reaction was monitored by tlc (ether, MeOH). After 6 d, the reaction was completed and the reaction product was purified by column chromatography over silica gel (18 cm, 30 g), eluting in 15 ml fractions.

The following eluents were used successively: ether 96, NH 4 saturated MeOH 4 fractions 1-49 92 8 fractions 50-57 86 14 fractions 71-90.

Fractions 50-57 contained the desired reaction product 1c (108mg).

The sulfate was prepared by precipitation with ether (2% / ethanol).

UV spectrum of the sulfate (CH ^ OH) max: 224 (4.63) - 272 (4.32) 35 min: 247 (4.03) shoulders: 286 (4.22) - 312 (3.72) IR spectrum (KBr) of the sulfate: 3420 - 3060 - 2960 - 2930 - 2880 - 2600 (weak) - 8204 71 1 F -.................... . ", ..,. .......

- 11 - 1725 - 1660 - 1615 - 1500 - 1455 - 1430 - 1375 - 1230 - 1105 -1060 - 1015 - 920 - 745 cm ”1.

NMR spectrum (CDCl 3) 360 MHz of the base in ppm; 9.46 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.53 ( d, 1H), 7.30 (d, 1H), 6.51 (s, 1H), 6.04 (s, 1H), 4.94 (q, 1H), 4.18, (d, 1H) , 4.05 (q, 2H), 3.77 (s, 3H) / m approximately s-centered around 5.81.

EXAMPLE III

Ethyl N- (0-4-deacetyl-4'-deoxyvinblastin-23-10, oyl-B) isoleucinate.

A solution of 0-4-deacetyl-4'-deoxyvinblastin-B-hydrazide (0.6g, 0.79mnol - see U.S. Patent No. 4,203,898, column 24, line 51) in a 15ml mixture CH 2 OH and 45 ml 1N HCl were cooled to -7 ° C. NaNOj (0.15 g) was added to the solution and stirring at -7 ° C was continued for 13 min. After adding an aqueous saturated solution of NaHCO 2 until a pH value of 9 was reached, the resulting solution was extracted four times with CH 2 Cl 2. The combined organic phases were washed with saturated aqueous NaCl solution and dried over MgSO 2 .

The solution was concentrated to a volume of 15 ml and ethyl isoleucinate (1.25 mmol) was added.

The reaction mixture was left in a refrigerator for 4 d. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiO 2, 60 g) and eluted with ether / CH 3 OH / NH 3 (96: 4). 0.25 g of an amorphous product (yield 35%) were thus obtained.

Mass spectrum: (molecular ionization isobutane) 30 880 (M +), 894, 836, 849, 832, 445, 391, 355 cm "1

Melting point; 180-190 ° C.

αD = 104 ° (c = 0.154) IR (CHCl-) 3470, 2970, 1728, 1655, 1612, 1502 cm-1 UV (CH 3 OH) 289, 268, 216 nm NMR (CDCl 3) 7 7.9 (NH) , 654 and 6.06 Hg, Ηχ2, 5.81 (H14-Hl5), 4.60 (CHCO2 (NH)), 3.76 O ^ CH ^ 3.58 0Η3 ~ Ο, 3.33 and 2.85 (H3A and H3B), 2.73 (N-CH3), 0.69 (H-15 ').

8204711 - 12 -

Acute toxicity determination of LD, .q

The acute toxicity of the compound of Example II: ethyl N- (0-4-deacetyldeoxy-4'-vinblastin-23-oyl-B) -tryptophanate was determined on NMR1 female mice. Increasing doses of the drug were inoculated intravenously via a single injection. The mortality rate was determined as a function of time. The LD 2 values for the above-mentioned compound (deoxy VTrpE) and a comparative product: deoxyvinblastine (deoxy VBL) are shown below.

10 ~ 50 drug

Deoxy-VBL 20

Deoxy-VTrpE (i.e. 91.5 compound lc)

Thus, the deoxy-VTrpE compound is less toxic than the comparative compound.

Anti-tumor activity

The chemotherapeutic activity of the sulfate salt of deoxy-VTrpE has been studied with respect to lymphoblastic leukemia L 1210 and P 388.

20 1. L 1210 4

Female DBA2 ”mice were inoculated with 10 leukemic cells. The product was administered intravenously at a dose of 50 mg / kg the day after inoculation.

Animal mortality was monitored as a function of time. Table A shows the results obtained with the compound of Example II (1c). At the tested dose, the compound is more active than vinblastine. This superiority was confirmed over deoxyvinblastine.

2. P 388 Female DBA mice were inoculated intravenously with 10 leukemic cells. The products were injected i.v. administered. Animal mortality was observed as a function of time. The results are shown in Table A. Deoxy VTrpE is clearly more active than the comparative compound and shows a higher percentage of long-term surviving animals.

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8204711

Claims (11)

1. Vinblastine derivatives of the general formula 2 of the formula sheet, wherein R is an amino acid ester, which is optionally protected, bound to the vinblastin-23-oyl radical 5 by an amide bond, the straight or branched ester group containing 2-9 carbon atoms and a hydrogen atom or a hydroxy group, R2 is a hydrogen atom, a formyl group or a C2-C8 acyl group, Rg is a hydrogen atom or a methyl group or a formyl group, with the proviso that compounds wherein Rg is methyl and R ^ a β group is excluded; or their addition salts with mineral or organic acids. 2. Vinblastine derivatives of the general formula 3 of the formula sheet, in which R 1 is a hydroxy group or a hydrogen atom, R 2 is a hydrogen atom, a formyl group or a C 2 -C 6 acyl group, R g is independently considered a hydrogen atom, straight or branched C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, aminohydroxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkyl, amido-C 1 -C 8 -alkyl, guanadino-C 1 -C 8 -alkyl, amino -C 1 -C 8 alkyl, thiol-20 C 1 -C 8 alkyl, cysteinylmethyl, methylthioethyl, benzyl, hydro-xybenzyl, or a group of formula 4 or 5 of the formula sheet, or Rg together with the carbon to which it bonded to form the nitrogen atom of the amido group, an azole or a hydroxyazole ring; Rg is a hydrogen atom or a methyl-25 group or a formyl group and R4 is a straight or branched C 1 -C 6 alkyl, or a benzyl group, the simultaneous meanings Rx being β-ΟΗ and Rg being -CHg; or their acid addition salts with mineral or organic acids. 3. Ethyl or methyl N- (O-4-deacetylvincristin-30-23-oyl) -L-tryptophanate or their addition salts with pharmaceutically acceptable acids. 4. Ethyl or methyl N- (0-4-deacetyldeformyl-vincristin-23-oyl) -L-tryptophanate or their addition salts with pharmaceutically acceptable acids. 5. Ethyl N- (0-4-deacetyldeoxyvinblastin-23-B-oyl) -L-tryptophanate or its addition salts with pharmaceutically acceptable acids. Compounds according to any one of claims 1-5, 8204 71 1 - 15 - characterized in that the addition salt is the 1: 1 addition salt with sulfuric acid. Pharmaceutical composition for use in medicine or veterinary science for the treatment of neoplastic diseases, characterized in that it contains one or more of the compounds according to any one of claims 1-6. Pharmaceutical composition according to claim 7, in a dosage form, wherein the active compound 10 is present in an amount of about 2-900 mg for a unit dose. Pharmaceutical composition according to claim 7, wherein the active compound is ethyl-N- (0-4-deacetyl-vincristin-23-oyl) -L-tryptophanate or its addition salt with a pharmaceutically acceptable acid. Pharmaceutical composition according to claim 7, wherein the active compound is ethyl-N- (0-4-deacetyldeformylvincristin-23-oyl) -L-tryptophanate or its addition salt with a pharmaceutically acceptable acid. A pharmaceutical composition according to claim 7, wherein the active compound is ethyl-N- (0-4-deacetyl-deoxyvinblastin-230-oyl) -L-tryptophanate or its addition salt with a pharmaceutically acceptable acid. 25 8204711