CH655727A5 - N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM. - Google Patents

Description

The present invention relates to novel bisololic alkaloids. More particularly, the invention relates to new products for coupling amino acids with vinblastine derivatives, and to pharmaceutical compositions containing them.

These new vinblastine derivatives can be used for the treatment of leukemia and malignant tumors in humans.

Bisindolic alkaloids of the vinblastine type are well known compounds having the carbon skeleton of the following general formula:

(I)

OH

OR

»If00

Ö

(V)

or R3 represents, with the carbon atom to which it is attached and the nitrogen of the amide group, an azole or hydroxyazole ring; R5 represents a hydrogen atom, a methyl group or a formyl group, and R4 represents a linear or branched alkyl group having from 1 to 8 carbon atoms, or a benzyl group, excluding the compounds where Ra = ß-OH and Rs = CH3, as well as their addition salts with mineral or organic acids.

3. Compounds according to claims 1 and 2, characterized in that it is N- (deacetyl-0-4 vincristinoyl-23) -L-tryptophanate

23 Ç "°

By way of example, mention will be made of vincaleukoblastine (American patent-65 eain N 3097137), leurocristine or vincristine and leurosidine (American patent N 3205220). vinglycinate (Belgian patent N 659112) and vindesine (Belgian patent N 813168). The latter compound was obtained by chemical transformation of vinblastine

3

655,727

natural (I. R, = OCH3, R2 = COCH3), which itself is obtained by extraction from the leaves of Catharanthus roseus.

Vinblastine, vincristine and vindésine are marketed for their use in human therapy, more particularly for the treatment of leukemias and certain solid tumors.

These drugs nevertheless have unfavorable side effects. Vincristine is neurotoxic and vinblastine is highly toxic in the hematopoetic tissue.

Their mechanism of action is analogous to that which has been postulated for the antimitotic action of colchicine. These drugs would act by inhibiting the polymerization of tubulin into microtubules and subsequent arrest of cell division in metaphase.

The use of 1: 1 complexes of bisindolic antitumor alkaloids with tubulin has been described in Belgian Patent No. 854053.

In some cases, this may result in less toxicity and greater chemotherapeutic activity than that of the corresponding free alkaloids.

Other derivatives obtained by chemical modification of vinblastine have been tested. Thus vinglycinate sulfate (I, sulfate, Rj = OCH3, R2 = COCH2N (CH3) 2j "Cancer Research", 1967, 27, 221-227) was studied in clinical experimentation but generally did not appear to be superior to vinblastine and vincristine.

Belgian patent No. 813168 describes vindesin (I, R5 = NH2, R2 = H) and other C3 carboxamide derivatives of vinblastine. Subsequent publications have confirmed the therapeutic value of vindesine or carboxamide-3 deacetyl-O-4 vinblastine, but this compound has nonetheless proved inactive for the treatment of L 1210 tumors transplanted in mice (CJ Barnett et al., "J. Med. Chem." 21, 88, 1978).

The new compounds described in the present invention are capable of effectively delaying the death of mice to which P 388 and L 1210 tumors have been transplanted intravenously.

The activities on these experimental P 388 tumors have surprisingly been found to be much superior to those of the reference Vinca alkaloids. Many complete remissions have been observed.

The derivatives of the invention also have other important and unexpected advantages compared to vinblastine and its known analogues, in particular vindesine.

In particular, the toxicities observed are generally lower than those corresponding to vindesine or vincristine.

The present invention relates to vinblastine derivatives corresponding to the following general formula II:

(II)

The new compounds of the invention more particularly correspond to general formula III:

(III)

wherein Rt represents a hydroxyl group or a hydrogen atom, R2 represents a hydrogen atom, an acyl or formyl group having from 1 to 9 carbon atoms; R3 represents each time, independently, a hydrogen atom, a branched or unbranched alkyl group containing from 1 to 8 carbon atoms, a hydroxy group C1-C8 alkyl, aminohydroxy C1-C8 alkyl, carboxy C1-C8 alkyl, amido C1 -C8 alkyl, guanadino C1-C8 alkyl, amino 25 C1-C8 alkyl, thiol C1-C8 alkyl, cysteinylmethyl, thiomethylethyl, benzyl, hydroxybenzyl,

Oer

I (IV)

H

: h „-

(V)

or R3 represents, with the carbon atom to which it is attached and the nitrogen of the amide group, an azole or hydroxyazole ring; R5 represents a hydrogen atom, a methyl group or a form group

35 myle, and R4 represents a linear or branched alkyl group having from 1 to 8 carbon atoms, or a benzyl group, excluding the compounds where R] = ß-OH and R5 = CH3, C00R4 preferably represents a group carboethoxy or carbomethoxy, as well as their addition salts with mineral or organic acids.

40 More particularly, the structural fragment of formula (III):

R, O

-nh-ch-cor4

(III)

represents an ester of any of the natural amino acids and their optical isomers of configuration D, in particular:

glycine so alanine valine leucine isoleucine serine 55 threonine hydroxyproline aspartic acid glutamic acid asparagine glutamine arginine lysine cysteine hydroxylysine cystine methionine phenylalanine tyrosine tryptophan proline histidine in which R represents an amino acid ester, optionally protected, linked to the vinblastin fragment amide, the branched or unbranched ester group having from 2 to 9 carbon atoms, R represents a hydrogen atom or a hydroxyl group, R2 represents a hydrogen atom, a formyl or acyl group comprising from 2 to 9 atoms carbon, R5 represents a hydrogen atom, a methyl group or a formyl group, excluding the case where Rs represents a methyl group and R] represents a ß-hydroxyl group as well as its addition salts with mineral acids or organic.

These compounds can be considered to be derivatives of descarbomethoxy-3 deacetyl-O-4 vinblastine carboxamide-3. However, it will be preferred to designate them as N- (vincris-tinoyl-23) derivatives (corresponding to the compound of formula II or III in which R5 = formyl (CHO) and Rj = OH), or N- (vinblastinoyl-23- B) (corresponding to the compound of formula II or III in which Rj = methyl and R! = H, the letter B signifying that Rj is in posi-65 tion a and that the ethyl chain 4 'is in position ß of a point stereochemical) of amino acids.

The preferred compounds of the invention correspond to formula II in which R2 represents a hydrogen atom and the acid part

655727

4

amino acid is derived from one of the following amino acids: "L or D trvpto-phane, leucine, valine, isoleucine, alanine and phenylalanine. Among these, L-tryplophan, L-isoleucine and L-alanine have been found more particularly interesting.

The present invention more particularly discloses amino acid coupling products with vincristine, deacetyl-O-4 vincristine, deformyldesacetyl-O-4 vincristine and deoxyvin-blastin ß.

The latter compound can be obtained by hydrogenation of the an-hydrovinblastine obtained by dehydration of vinblastine or by coupling of vindoline with catharantine (Potier et al., JACS 98, 7017, 1976). The preferred compound of the present invention is ethyl N- (deacetyl-0-4 deoxy-4'-vinblastinoyl-23) tryptophanate.

When the amino acid contains functional groups in the R3 side chain (formula III), such as lysine or cysteine, it may be necessary to protect these functional groups using methods well known to those skilled in the art.

This protection can be carried out, depending on the nature of the group to be protected, by grafting a benzyl, t-butyl, benzyloxy-carbonyl group. t-butoxytrifluoroacetylcarbonyl or trityl. Other agents well known in peptide chemistry can be advantageously used.

According to the process mentioned above, the compounds according to the invention can be obtained from the corresponding derivatives of vinblastine, in a conventional manner, by hydrazinolysis followed by ni-trosation, then coupling with the amino acid ester according to the reaction scheme I:

4 ^

OCOCH,

N, H,

CH3OH

Diagram I

P-, NaNO,

HCl

COOCH-

amino acid ester

CH, C1,

HO C-N_

C- N-C-CO -OR,

I 4

H

The first step is to add an excess of anhydrous hydrazine to a solution of vinblastine base in anhydrous methanol. The reaction mixture is then heated under an inert atmosphere for 12 h at 12 d at a temperature between 30 and 70: C. Preferably, the temperature will be maintained at around 60: C.

The hydrazide of the bisindolic derivative is then isolated by addition of water, extraction with dichloromethane and concentration. The compound can be further purified by preparative chromatography (neutral silica). In the case of vincristine, the product obtained is 0-4 desacétyldésformylvincristine carboxhydrazide.

In the second step, the hydrazide function of the modified vinblastine is transformed into acid azide. This transformation is carried out, in a known manner, by adding sodium nitrite to the hydrazide in solution in a methanol, acid water mixture.

The acid used can be hydrochloric acid.

The reaction temperature is maintained between 0 and 5: C. After extraction with an aprotic solvent which is not soluble in water, preferably methylene chloride, the organic phase is partially concentrated.

The acid azide itself is preferably not isolated, but directly brought into contact with the amino acid ester or, where appropriate, the corresponding protected derivative, in solution in methylene chloride.

The amount of amino acid used is 1 to 5 equivalents of modified vinblastine carboxazide.

The reaction medium is maintained between -3 and + 10 ° C. for 8 to 72 h. usually around 3 p.m. The reaction is easily followed by thin layer chromatography. After concentration, the compound of invention III is isolated, which can be transformed into sulphate or another mineral or organic acid salt by crystallization from a methanolic solution of the corresponding acid.

The compounds of the invention are purified using well known techniques of chromatography and recrystallization. If necessary, the deacetyl-O-4 derivative vinblastine thus obtained can be reacetylated either directly to give the derivative of vinblastine II in which R2 - COCH, ("J. Med. Chem.". 22, 391, 1979 ) or by preliminary formation of the diacetoxy-3,4 derivative followed by a selective hydrolysis of the acetoxy group in position 3. The C 4 hydroxyl group can be, in a manner known per se, esterified by other activated derivatives of acids comprising 2 to 9 carbon atoms. The formylated 0-4 derivatives are obtained by formylation (formic acid-acetic anhydride) of the corresponding 0-4 deacetyls; see Belgian patent No 660843.

The present invention also extends to industrial and in particular pharmaceutical applications of new bisindolic compounds.

The compounds of the invention present in particular particularly useful antitumor properties which can be used in human therapy.

These amino acid derivatives can, in particular, be used for the treatment of leukemias of the L 1210, P 388 type, of gliomas, lymphosarcomas and other leukemias or malignant tumors.

In human therapy, they are used for the treatment of Hodgkin's disease and for other tumors which may benefit from treatment with vinblastine, vincristine and vindesine.

These compounds can also be used in veterinary medicine for the treatment of tumors in animals.

Other interesting therapeutic applications can be envisaged for these new derivatives of bisindolic alkaloids. It has in fact been noted that vinblastine could be used in the treatment of certain arthritis (United States patent No. 4208411) and vincristine for the treatment of psoriasis (United States patent No. " 3749784).

For their therapeutic application, the compounds of the invention, optionally in lyophilized form, are preferably administered parenterally, dissolved in a pharmaceutically acceptable solvent, in the form of a base or of an addition salt. a pharmaceutically acceptable acid. Among the addition salts, the non-toxic, pharmaceutically acceptable salts, such as the salts of mineral acids such as hydrochloric acid, phosphoric acid and sulfuric acid, or organic acids such as acetic, propionic, suecinic, tartaric, oxalic, methanesulfonic, benzenesulfonic acid.

se Physiological water or other buffered saline solutions, for example with phosphate, are suitable solvents. In general, these compounds can be used drawing inspiration from the techniques and limitations which are known for therapeutic treatments with the other alkaloids of the 55 Vinca class.

The active substance is generally administered at a dosage which can vary from 0.01 mg to approximately 5 mg / kg, depending on the derivative used and the therapeutic regimen adopted. Total weekly doses will generally range from 0.1 mg to approximately 35 mg / kg. The compositions according to the invention are presented in administration forms containing the active principle at a unit dose of 2 to 900 mg.

The compounds of the invention can be used alone or in combination with one or more carcinostatic agents including, for example, alkylating agents, antimetabolites such as me-thotrexate, fluoro-5-uraeiIe. mercapto-6-purine, thio-6-guanine, cytosine arabinosides and antibiotics such as actinomycin D, daunorubicin. adriamvcine, and cis-diamino-

5

655111

dichloro-platinum. In particular, these new vinblastine derivatives can be used in combination with one another.

The following examples illustrate, without limitation, the process leading to the compounds of the invention.

Example 1

1. Preparation of 0-4 deacetyl-N-desformylvincristine monohydrazide A

985 mg of vincristine base are dissolved in a mixture of 10 ml of anhydrous hydrazine and 10 ml of methanol. The reaction medium is brought to 60 ° C. with stirring for 22 h. The reaction mixture is then treated with water and then with water saturated with NaCl. The aqueous solution is extracted 8 times with 15 ml of dichloromethane. The combined organic phases are treated with 20 ml of water and then 25 ml of water saturated with NaCl and then dried over Na2SO4. After filtration and concentration under vacuum, 900 mg of 0-4 de-acetylvincristin monohydrazide is obtained (purity greater than 90%).

Nuclear magnetic resonance spectrum (CDC13) 360 MHz (ppm): 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 impact ionization): 154, 294, 355, 413, 524, 555, 695, 710, 723, 736, 739, 755 (M + 1) - 768, 769, 782.

Calculated for C42H54N607: 754, 942.

2. Preparation of the modified azcristine acid azide

A solution of 850 mg of vincristine monohydrazide A in 20 ml of methanol is treated with 63 ml of IN HCl and 175.5 mg of sodium nitrite for 15 min at 0 ° C.

The solution, maintained at 0r C, is then neutralized with NaHCO 3 at 0r C and then extracted six times with 15 ml of dichloromethane. The combined organic phases are dried over Na2SO4, filtered and then concentrated in vacuo without heating until a solution of approximately 10 ml is obtained.

3. Coupling with ethyl tryptophanate

300 mg of ethyl tryptophanate are then added with stirring at approximately 47 ° C. and the reaction is followed by TLC. After 10 d, the coupling product is purified by chromatographic separation (40 g Silicagel 60, ether / methanol elution solvent saturated with NH3, 96/4, v / v). 15 ml fractions are thus collected which are controlled by TLC. The uncoupled amino acid is first collected (fractions 30 to 40). The eluent is changed (ether / methanol saturated with NH3, 86/14) and the coupled derivatives are collected in three portions: fractions 44 and 45 30 mg, fractions 46 to 53 257 mg, fractions 54 to 60 115 mg.

The second portion consists of N- (0-4 deacetyldesfor-mylvincristine-23-oyl) ethyl tryptophanate the homogeneous TLC.

Mass spectrum: 984, 970, 956 (M * + 1), 913, 912, 899 (DCJ isobutane).

Calculated for CssH ^ NgOg: 955, 181.

Spectrum (/ F (CH3OII):

Max: 282 (4.20), 290 (4.18), 322 (3.96).

Min: 254, 287, 305.

IR spectrum (cm ~ '): 3400, 2920, 1720, 1660, 1610, 1485, 1450, 1370, 1345, 1330, 1290, 1220, 1165, 1130, 1025, 1005, 920, 885, 830, 740.

NMR spectrum (CDC13) 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).

N-f 0-4 deacetylvincristin-23-oyl) ethyl tryptophanate Ib

The deformylated derivative la (257 mg) is reformylated by applying the method described in Belgian patent No. 811110.

The crude product thus obtained is purified by chromatographic separation using successively 3 eluents: ether / MeOH saturated with NH3, 92.8, 88/12, 86/14. The effluent is collected in 15 ml fractions. Fractions 44 to 54 (34.1 mg) contain the derivative N-refor-5 mylé Ib.

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

Calculated for C56HöüN6O10: 983, 192.

Spectrum t / F (CH3OH):

10 Max: 270 (4.18), 290 (4.11).

Plate 280 (4.12), shoulder (4.03).

IR spectrum (KBr): bands at 3400, 3040, 2960, 2920, 2880, 2850, 1735, 1725, 1680, 1670, 1665, 1610, 1490, 1450, 1225, 745.

Example 2

N-f 0-4 deacetyldoxy-4'-vinblastin-23-oyl-fi) ethyl tryptophanate le

0-4 desacétyldésoxyvinblastine hydrazide is prepared according to the procedure set out in US Patent No. 4203898 (Lilly, column 24, line 51 et seq.).

500 mg of hydrazide in 12 ml of methanol are then treated with 37 ml of IN HCl and 104 mg of NaNO2 for 15 min at 0 ° C.

The solution is then neutralized with NaHC03 and then extracted six times 25 times with 15 ml of dichloromethane. The organic phases are dried over Na2SO4 and concentrated until a volume of approximately 10 ml is obtained.

The azide in solution is then placed in the presence of ethyl tryptophanate (300 mg) at 4 ° C. with stirring. The reaction is followed by TLC (ether, MeOH). After 6 d, the reaction is terminated and the coupling product is purified by column chromatography on Silicagel (18 cm, 30 g), elution in 15 ml fractions.

The following elected officials were successively used:

ether 96 MeOH saturated with NH3 4 fractions 1 to 49 35 92 8 fractions 50 to 57

86 14 fractions 71 to 90

Fractions 50 to 57 contain the desired coupling product (108 mg) le.

4D The sulfate is prepared by precipitation in ether.

(2% H2SO4 / ethanol.)

UV spectrum of sulfate (CH3OH):

Max: 224 (4.63), 272 (4.32).

43 Min: 247 (4.03).

Shoulder: 286 (4.22), 312 (3.72).

IR spectrum (KBr) of sulfate: 3420, 3060, 2960, 2930, 2880, 2600 (low), 1725, 1660, 1615.1500, 1455, 1430, 1375, 1230, 1105, 1060, 1015. 920, 745 cm " '.

50

NMR spectrum (CDC13) 360 MHz of the base (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), almost m s centered on 5.81, 4.94 (q, 1H), 4.18 (d, 1H), 4.05 (q, 2H), 3.77 (s, 3H), 3.58 (s, RH ), 55 3.47 (s, 1H), 2.82 (s, 2H), 2.77 (s, 3H), 2.59 (s, 1H), 1.14 (t, 3H), 0, 95 (t, 3H), 0.87 (t, 3H).

Base mass spectrum (INN isobutane): M + 1 + at 14 + 1 + at 968. M + 28 + 1 "at 982; ions at 153, 155, 157, 171, 172, 185, 186, 60 199, 213, 223, 227, 255, 257, 279, 281, 283, 285, 349, 398, 459, 516, 569, 952, 953, 955, 967, 969, 981, 983.

Calculated for C5ûH68N608: 953, 208.

Example 3

65 N- (0-4 deacetyl-4'-deoxyvinblastin-23-oyl-P) ethyl isoleucinate

A solution of 0-4 deacetyl-4'-desoxyvinblastin-p hydrazide [0.6 g: 0.79 mN (see American patent N "4203898, column 24,

line 51] in a mixture of 15 ml of methanol and 45 ml IN HCl is

655,727

6

cooled to -7 C. 0.15 g of NaNO2 is added to the solution and stirring is continued for 13 min at -7 ° C. After addition of a saturated aqueous solution of NaHCO3 until reaching a pH of 9, the solution obtained is extracted four times with CH2C12. The combined organic phases are washed with saturated NaCl solution and dried over MgSO4.

The solution is concentrated to a volume of 15 ml and ethyl iso-leucinate (1.25 mN) is added to it. The solvent is then evaporated under reduced pressure. The residue is purified on a chromatography column (SiO2, 60 g) and eluted with ether CH3OH / NH3 (96/4). io 0.25 g of an amorphous product is obtained (yield 35%).

Mass spectrum (isobutane molecular ionization): 880 (M "), 894, 836, 849, 832, 445; 391, 355 cm" '.

Calculated for C5iH6gNs08: 880.1 I5

Melting point: 180-190 C.

ctD = 104 ° (c = 0.154).

IR spectrum (CHC13): 3470, 2970, 1728, 1655, 1612, 1502 cm '.

Spectrum t / K (CH3QH): 289, 268, 216 nm. 20

NMR spectrum (CDC13): 7.9 (NH), 6.54 and 6.06 (H9, HJ2), 5.81 (H14-H, s), 4.60 (CHC02 NH), 3.76 (C02CH3 ), 3.58 (CH3-0), 3.33 and 2.85 (H3A and H3B), 2.73 (N-CH3), 0.69 (H-15 ').

25

Acute toxicity - Determination of LD, „,

The acute toxicity of the compound of Example 2 N- (0-4 deacetyl-deoxy-4'-vinblastine-23-oyl-P) ethyl tryptophanate was studied in female NMRI mice. Increasing doses of the drug are administered intravenously as one injection. The percentage 30

mortality is monitored over time. The LD50 values obtained for the compound of Example 2 (deoxy VTrpE) and a reference product (deoxyvinblastin = deoxy VBL) are given below:

Drug LD50 Deoxy VBL 20 Deoxy VTrpE (le) 91.5

The deoxy derivative VTrpE is therefore less toxic than the reference compound.

Antitumor activity

The chemotherapeutic activity of the deoxy sulfate salt VTrpE has been studied on lymphoblastic leukemias L 1210 and P 388.

1. L 1210

Female DBA2 mice are inoculated with 104 leukemia cells. The product is administered intravenously the day after the transplant at a dose of 50 mg / kg. The mortality of the animals is monitored as a function of time. Table 1 shows the results obtained with the compound of Example 2 (Ie). At the dose tested, the derivative is more active than VBL. This superiority has been confirmed compared to the VBL deoxy.

2. P 388

Female DBA2 mice receive 104 leukemia cells intravenously. The products are administered i.v. the day after the transplant. The mortality of the animals is monitored over time. The results are shown in Table 1. The VTrpE deoxy is clearly more active than the reference compound and has a very large percentage of long-term survivors.

Table 1

Tumor

Product

Dose

Number of animals

MST day

THEY

%

Percentage of survivors at day 30

Percentage of survivors on day 60

L 1210

LAV

8

10

10.4

57.6

0

0

LAV

9

10

5.8

-21.6

0

0

Deoxy VTrpE

50

10

11.2

70

0

0

P 388

VBL deoxy

4

5

15.6

56

0

0

VBL deoxy

8

5

5.8

-42

0

0

Deoxy VTrpE

30

10

16.5

58.7

0

0

40

15

30

191

67

53

50

15

30

191

87

73.3

55

10

30

212

80

60

60

10

30

212

90

90

Female DBA2 mice are inoculated i.v. with 104 leukemia cells. The drugs are administered i.V. at specified doses and schedules.

MST = median survival time = average day of survival.

ILS% =% of increase in life span = percentage increase in survival time.

Claims (10)

655,727 2 1. Vinblastine derivatives corresponding to the following general formula (II): (II) in which R represents an amino acid ester, optionally protected, coupled to the vinblastinoyl-23 fragment by an amide link, the branched or unbranched ester group having from 2 to 9 carbon atoms, R represents a hydrogen atom or a hydroxyl group, R2 represents a hydrogen atom, a formyl or acyl group having from 2 to 9 carbon atoms, R5 represents a hydrogen atom, a methyl group or a formyl group, excluding the case where R5 represents a methyl group and Rj represents a β-hydroxyl group, as well as its addition salts with mineral or organic acids. 2. Compounds according to claim 1 represented by the general formula (III): 20 (III) in which R represents a hydroxyl group or a hydrogen atom, R2 represents a hydrogen atom, an acyl or formyl group having from 1 to 9 carbon atoms; R3 represents each time, independently, a hydrogen atom, a branched or unbranched alkyl group containing from 1 to 8 carbon atoms, a hydroxy group C1-C8 alkyl, aminohydroxy C1-C8 alkyl, carboxy C1-C8 alkyl, amido C1 -C8 alkyl, guanadino C1-C8 alkyl, amino C1-C8 alkyl, thiol C1-C8 alkyl, cysteinylmethyl, thiomethylethyl, benzyl, hydroxybenzyl, ethyl or methyl and its addition salts with pharmaceutically acceptable acids. 4. Compounds according to claims 1 and 2, characterized in that it is N- (deacetyl-0-4 desformylvincristinoyl-23) -L-tryptophanate of ethyl or methyl and its salts addition with pharmaceutically acceptable acids. 5. Compounds according to Claims 1 and 2, characterized in that it is ethyl N- (deacetyl-0-4-deoxyvinblastinoyl-23-B) -L-trypto-phanate, and its salts addition with pharmaceutically acceptable acids. 6. Compounds according to one of claims 1 to 5, characterized in that they are addition salts 1: 1 with sulfuric acid. 7. Pharmaceutical composition used in human and veterinary medicine for the treatment of neoplastic diseases, characterized in that it contains one or more derivatives defined in one of claims 1 to 6. 8. Pharmaceutical composition according to claim 7, characterized in that it is in the form of administration in which the active principle is present in a unit dose of between 2 and 900 mg. 9. Pharmaceutical composition according to claim 7, characterized in that the active principle is N- (deacetyl-0-4 vincristi-noyl-23) -L-tryptophanate ethyl, optionally in the form of a salt addition with a pharmaceutically acceptable acid. 10. Pharmaceutical composition according to claim 7, characterized in that the active principle is N- (deacetyl-0-4 desfor-mylvincristinoyl-23) -L-tryptophanate ethyl, optionally in the form of a salt addition with a pharmaceutically acceptable acid. 11. Pharmaceutical composition according to claim 7, characterized in that the active principle is N- (deacetyl-0-4 deoxy-vinblastinoyl-23 B) -L-ethyl tryptophanate and the corresponding sulfate.