FR2517680A1 - N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

COMPOUNDS OF THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS AN AMINO ACID ESTER, POSSIBLY PROTECTED, COUPLED TO THE VINBLASTINOYL-23 FRAGMENT BY AN AMID BOND, THE ESTER GROUP, BRANCHED OR NOT HAVING FROM 2 TO 9 ATOMS OF CARBON, R REPRESENTS A HYDROGEN ATOM OR A HYDROXYL GROUP, R REPRESENTS A HYDROGEN ATOM, A FORMYL OR ACYL GROUP WITH 2 TO 9 CARBON ATOMS, R REPRESENTS A HYDROGEN ATOM, A METHYL GROUP FORMYL, EXCLUDING THE CASE OR R REPRESENTS A METHYL GROUP AND R REPRESENTS A B-HYDROXYL GROUP AS WELL AS ITS ADDITIONAL SALTS WITH MINERAL OR ORGANIC ACIDS. APPLICATION TO THE PHARMACEUTICAL INDUSTRY.

Description

Derivatives N- (vinblastinoyl-23) of amino acids, their preparation and

their therapeutic application.

  The present invention relates to novel bis-indole alkaloids. More particularly, the invention relates to novel products.

  of amino acid coupling with derivatives of wine-

  blastine, their process of preparation, their application

  cation as antitumor agents and to

  pharmaceutical preparations containing them.

  These new derivatives of vinblastine can be used for the treatment of leukemias and

malignant tumors in humans.

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

OH

CH 3 2

I (I)

C 30 C OR,

J HO s

23 C = O

R 1 c

  For example, vincaleuko-

  blastine (U.S. Patent 3,097,137), desocristine or vincristine and leosidine (U.S. Patent 3,205

  220), vinglycinate (Belgian Patent 659 112) and wine-

  The latter compound was obtained by chemical transformation of natural vinblastine (I, R 1 OCH 3, R 2 X COCH 3), which itself is

  obtained by extraction from Catharan leaves

thus roseus.

  Vinblastine, vincristine and wine

  are marketed for their use in human therapy, more particularly for the

  treatment of leukemias and certain solid tumors.

  These drugs, however, have adverse side effects Vincristine is neurotoxic and vinblastine is highly toxic

  at the level of hematopoietic tissues.

  Their mechanism of action is similar to that which has been postulated for antimitotic action

  colchicine These drugs would act by inhibiting

  tubulin polymerization into microtubules

  and subsequent cessation of cell division into metapha-

  is. The use of 1: 1 complexes of antitumor bisindole alkaloids with tubulin has been described

in the Belgian patent 854 053.

  In some cases, this may result in lower toxicity and more chemotherapeutic activity.

  important than those of the corresponding free alkaloids.

  Other derivatives obtained by chemical modification of vinblastine have been tested. Thus, vinglycinate sulfate (I, sulfate, R1 OCH3, R 2 COCH 2 N (CH 3) 2, Cancer Research 1967, 27, 221-227) has It has been studied in clinical trials but has not generally been shown to be superior to vinblastine and vincristine. Belgian Patent 813 168 describes vindesine (I, R 1 NH 2, R 2 = H) and other C 3 carboxamide derivatives of vinblastine. Posterior publications have confirmed the therapeutic interest of vindesine or 3-carboxamide deacetyl. -0-4 vinblastine, but this compound was found to be inactive for the treatment of L 1210 tumors transplanted into mice (CJ Barnett

et al., J Med Chem 21, 88, 1978.

  The new compounds described in the pre-

  The present invention is capable of effectively delaying the death of mice transplanted by

  intravenous tumors P 388 and L 1210.

  Activities on these experimental tumors P 388 have surprisingly been very

  higher than those of reference Vinca alkaloids.

  Many complete remissions have been observed.

  The derivatives of the invention also possess

  other important and unexpected comparative advantages

  with vinblastine and its known analogues, in par-

especially vindesine.

  In particular, the toxicities observed are generally lower than those corresponding to the

vindesine or vincristine.

  The present invention relates to the derivatives of vinblastine corresponding to the following general formula II: embedded image in which R represents an amino acid ester, optionally protected, coupled to the vinblastinoyl-23 fragment by an amide bond, the branched or unbranched ester group having 2 to 9 carbon atoms, R 1 represents a hydrogen atom or a hydroxyl group, R 2 represents a hydrogen atom, a formyl or acyl group containing from 2 to 9 carbon atoms, R 5 represents a hydrogen atom, a methyl group or a formyl group, with the exception of the case where R 5 represents a methyl group and R 1 represents a P-hydroxyl group and its addition salts with mineral acids

or organic.

  The novel compounds of the present invention

  more particularly with the general formula III.

I

I (III)

Ca <3 e

5 C H-C OH R

  wherein R1 is hydroxyl or hydrogen, R 2 is hydrogen, acyl or formyl having 1 to 9 carbon atoms; R 3 represents independently, a hydrogen atom, a branched or unbranched alkyl group having 1 to 8 carbon atoms, a hydroxy group CI-C 8 alkyl, amino-hydroxy C 1 -C 8 alkyl, carboxy-CI- C 8 alkyl, amido C 1 -C 8 alkyl, guanadino C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, thiol C 1 -C 8 alkyl> cysteinyl methyl, thiomethyl-ethyl, benzyl, hydroxybenzyl, H 2 N or I or R 3 represents with the carbon atom to which it is attached and the nitrogen of the amide group, an azole or attached ring and the nitrogen of the amide group, an azole or hydroxyazole ring; R 5 represents a hydrogen atom, a methyl group or a formyl group, and R 4 represents a linear or branched alkyl group having from 1 to 8 carbon atoms, or a benzyl group, with the exception of the compounds R 1 = D 3 OH and R 5 CH 3, COOR 4 preferably represents a carboethoxy or carbomethoxy group, as well as their addition salts

  with mineral or organic acids.

  In particular, the structural fragment

ral of the formula III R R 3 's

-NH-CH-COR 4

  represents an ester of any of the natural amino acids and their optical isomers of configuration D, especially: glycine aspartic acid cystine alanine glutamic acid methionine valine asparagine phenylalanine leucine glutamine tyrosine isoleucine arginine tryptophan serine lysine proline threonine cysteine histidine

hydroxyproline or hydroxylysine.

  These compounds can be considered to be

  derivatives of descarbomethoxy-3-desacetyl-0-4 vinblas-

  tine carboxamide-3 However, we prefer to designate them

  as derivatives N- (vinblastinoyl-23) or N- (wine-

cristinoyl-23) amino acids.

  The preferred compounds of the present invention

  formula II wherein R 2 represents a hydrogen atom and the amino acid moiety is derived from one of the following amino acids: L or D tryptophan, leucine, valine, isoleucine, alanine and phenylalanine. Of these, L-tryptophan, L-isoeucine and L-alanine have been found to be particularly interesting. The present invention more particularly discloses amino acid coupling products with vincristine, desacetyl-0.4-vincristine,

  desformyl-desacetyl-0-4-vincristine and deoxy-vinblast-

  p. This last compound can be obtained by

  hydrogenation of anhydrovinblastine obtained by dehydration

  vinblastine or by coupling the vindoline

  catharantine (Potier et al, JACS 98 7017 1976).

  The preferred compound of the present invention is N- (desacetyl-04)

  4'-deoxy-vinblastinoyl-23) ethyl tryptophanate.

  When the amino acid contains functional groups in the R 3 side chain (Formula II), such as lysine or cysteine, it may be necessary to protect these functional groups using the

  methods well known to those skilled in the art.

  This protection may be effected, depending on the nature of the group to be protected, by the grafting of a

  benzyl, t-butyl, benzyloxycarbonyl, t-butoxy-

  trifluoroacetyl carbonyl 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, conventionally by hydrazinolysis followed by nitrosation, and then coupling with the amino acid ester according to the reaction scheme. I

N 2 H 4

CH Ot Na NO 2 HCl O C OH

HO C-N

"3 amino acid ester

CH CI 2

  The first step consists in adding 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 hours.

  at 12 days at a temperature between 30 and 70 C.

  Preferably, the temperature will be maintained around 60 ° C.

  The hydrazide of the bis-indole derivative is then isolated by addition of water, extraction with dichloromethane and concentration. The compound may be subsequently

  purified by preparative chromatography (neutral silica).

  In the case of vincristine, the product obtained is the

  0-4 desacetyl deformyl-vincristine carboxhydrazide.

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

  the hydrazide in solution in a water-methanol-acid mixture.

  The acid used can be hydrochloric acid

  drique. 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 derivative.

  protects, in solution in methylene chloride.

  The amount of amino acid used is

  from 1 to 5 equivalents of modified carboxazide vinblastine.

  The reaction medium is maintained between

  3 and + 10 OC for 8 to 72 hours, most often

  The reaction is easily followed by thin layer chromatography. After concentration, the compound of the invention II, which can be converted to sulphate or another salt of mineral or organic acid by crystallization from a methanolic solution, is isolated. of

the corresponding acid.

  The compounds of the invention are purified

  using the well-known techniques of chromatogra-

phie and recrystallization.

  If desired, the 0-4-vinylblastine deacetyl derivative thus obtained can be reacetylated either directly to give the vinblastine II derivative in which R 2 = COCH 3 (J Med Chem 22, 391, 1979) or by preliminary formation of 3,4-diacetoxy derivative followed

  selective hydrolysis of the acetoxy group at the 3-position.

  The C 4 hydroxyl group can be, in a manner known per se, esterified by other active derivatives of acids containing from 2 to 9 carbon atoms.

  Formylates are obtained by formylation (formic acid -

  acetic anhydride) of the corresponding 0-4 desacetyls,

see Belgian Patent 660 843.

  The present invention also extends to industrial and especially pharmaceutical applications

  new bisindole compounds.

  The compounds of the invention have, in particular, particularly antitumor properties.

  interesting and likely to be used in therapeutic

human tick.

  These amino acid derivatives can be, in particular, used for the treatment of leukemias of the L 1210, P 388, glioma, lymphosarcoma and other types of leukemia.

leukemias or malignant tumors.

  In human therapeutics, they are used for the treatment of Hodgkin's disease and for other tumors that may benefit from treatment with

  vinblastine, vincristine and vindesine.

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

with the animals.

  Other interesting therapeutic applications can be envisaged for these new bisindole alkaloid derivatives. It has indeed been noted that vinblastine could be used in

  treatment of certain arthritides (US Pat.

  United States No. 4,208,411) and vincristine for the treatment of psoriasis (United States Patent

No. 3,749,784).

  For their therapeutic application,

  compounds of the invention, optionally in lyophilic form.

  philisée are preferably administered by way of

  lateral, dissolved in a pharmaceutically

  acceptable, in the form of a base or an additive salt

  In the case of addition salts, non-toxic, pharmaceutically acceptable salts, such as acid salts, are preferred.

  minerals such as hydrochloric acid, phosphoric acid

  and sulfuric acid, or organic acids

  such as acetic acid, propionic acid, succinic acid, tartaric acid

  that, oxalic, methanesulfonic, benzenesulfonic.

  Physiological water or other buffered saline solutions, for example with a phosphate, are suitable solvents.

  compounds can be used, drawing on the techniques

  and limitations which are known for the treatment of

  treatment with other alkaloids in

class of Vinca.

  The active substance is usually administered

  at a dosage that may range from 0.01 mg to approximately

  5 mg / kg, depending on the derivative used and the treatment regimen

  The total weekly doses will vary widely

  typically from 0.1 mg to about 35 mg / kg.

  The compositions according to the invention are presented in administration forms containing

  the active ingredient at the unit dose of 2 to 900 mg.

  The compounds of the invention may be used alone or in combination with one or more carcinostatic agents including, for example, alkylating agents, antimetabolites such as methotrexate, fluoro-uracil, 6-mercapto-purine, thio-6

  guanine, cytosine arabinosides, and anti-

  biotic agents such as actinomycin D, daunorubicin,

  adriamycin, and cis-diamino-dichloro-platinum

  particular, these new derivatives of vinblastine

  can be used in association with each other.

  The following examples illustrate, in a nonlimiting manner, the process leading to the compounds

of the invention.

//

Example I 1

  Preparation of 0-4-desacetyl-N-desformyl-vincristine 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 hours.

  The action is then treated with water and then with

  NaCl solution The aqueous solution is extracted 8

  15 ml of dichloromethane.

  The combined fractions are treated with 20 ml of water and 25 ml of water saturated with NaCl and then dried over Na 2 SO 4. After filtration and concentration under vacuum

  900 mg of 0-4 desacetyl vincristine mono-

  hydrazide (purity greater than 90%).

  Nuclear Magnetic Resonance Spectrum (CDC 13.360MHz) 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), , 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 (2 t, 2 x 3H).

  Mass spectrum (ionization electronic impact)

  154, 294, 355, 413, 524, 555, 695, 710, 723, 736,

0 739, 755 (M + 1) 768, 769, 782

  calculated for C 42 H 54 N 607 754 942 2 Preparation of the acid azide of the modified vincristine. A solution of 850 mg of vincristine monohydrazide A in 20 ml of methanol is treated with 63 ml of 1N HCl and 175 mg of sodium nitrite for 15 minutes at 0 ° C. The solution, maintained at 0 ° C., is then neutralized with Na HCO 3 to OC then extracted six times with 15 ml

  of dichloromethane The organic phases collect

  are dried over Na 2 SO 4, filtered and then

  centered under vacuum without heating up to obtain

a solution of about 10 ml.

  3 Coupling with ethyl tryptophanate 300 mg of ethyl tryptophanate are then added with stirring at about 4 ° C. and the reaction is followed by tlc After 10 days, the product of

  The coupling is purified by chromatographic separation

  (40 g silica-gel 60, ether elution solvent, methanol sat in NH 96: 4, v: v). 15 ml fractions are thus collected which are controlled.

  by ccm The uncoupled amino acid is first re-

  collected (fractions 30 to 40) Eluent (ether, methanol sat in NH 3 86: 14) is changed and the coupled derivatives are reutilized in three portions: fractions 44 and 45 30 mg, fractions 46-53 257 mg, fractions

54-60 115 mg).

  The second portion consists of N- (0-4-deacetyl)

  desformyl-vincryline-23-oyl) ethyl tryptophanate

Ihe homogeneous in ccm.

  Mass Spectrum 899 (DCJ isobutane) 181.

984, 970, 956 (M '+ 1) 913, 912,

  calcd for C 55 H 66 N 609 955, UV Spectrum (CH 3 OH) max 282 (4.20) 290 (4.18) 322 (3.96) 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

NMR spectrum (CDC 1.

  8.50 (s, IHI) 8.03 (s, 2H) 7.77 (d, 1H) 7.60 (d, 1H) 7.57 (1H) 6.95 (1H) 6.35 (1H), 89 (dd, 1H), 78 (d, 1H) 4.75 (q, 1H) 3.88 (s, 3H) 3.67 (s, 3H) 1, 23 (t 311) 0.98 (t, 3H) 0.89 (t 13 H)

3) 360 MH

  (p pm) N- (O-4-desacetyl-vincristine-23-alkyl) -tryptophanate

of ethyl Ib.

  The deformyl derivative Ia (257 mg) is reformylated by applying the method described in the Belgian patent

811 110.

  The crude product thus obtained is purified by separation.

  chromatographic procedure using a column of

  20 cm (silica gel, 30 g) and using

  3 eluents: ether / Me OH sat in NH 3 92: 8, 88: 12, 86: 14 The effluent is collected in fractions of 15 ml Fractions 44 to 54 (34 1 mg) contain

the N-reformylated derivative Ib.

  Mass spectrum (DCI to isobutane): 1011, 997,

  983 (M + 1), 970, 982, 996, 998, 999, 1012.

  calculated for C 56 H 66 N 6010 983, 192.

  UV Spectrum (CH 3 OH) max: 270 (4.18) 290 (4.11) plateau 280 (4.12) shoulder (4.03) Spectrum I R (K Br)

  bands at 3400 3040 2960 2920 2880 2850 -

  1735 1725 1680 1670 1665 1610 1490 -

1450 1225 745.

Example 2

  N- (0-4-desacetyl deoxy 4 'vinblastine 23 alkyl -)

ethyl tryptophanate (Ic).

  O4-desacetyl deoxy vinblastine hydracid is

  trimmed according to the procedure described in the patent

  US 4,203,898 (Lilly, column 24 line 51 and following).

  500 mg of the hydrazide in 12 ml of methanol are then treated with 37 ml of 1N HCl and 104 mg of Na NO 2 during

'to O C.

  The solution is then neutralized with Na HCO 3 and then extracted six times with 15 ml of dichloromethane. The organic phases are dried over Na 2 SO 4 and concentrated.

  until a volume of about 10 ml is obtained.

  The azide in solution is then brought into contact with tryptophan

  ethyl phanate (300 mg) at 4 ° C. with stirring The reaction is followed by tlc (ether, MeOH) After 6 days the reaction is complete and the coupling product is purified by chromatography on a column of silica gel (18 cm, 30 g)

elution in fractions of 15 ml.

  The following eluents were successively used: ether 96 Me OH sat with NH 3 4 fraction 1 49 92 8 fractions 50 57

86 14 fractions 71 90.

  Fractions 50-57 contain the coupling product

desired (108 mg) Ic.

  The sulphate is prepared by precipitation in ether.

(2% H 2 SO 4 / ethanol).

2 4 ehao.

  UV Spectrum of sulfate (CH 3 H) max: 224 (4.63) 272 (4.32) min: 247 (4.03) shoulder: 286 (4.22) 312 (3.72) IR spectrum (K Br ) sulphate

3420 3060

1660 1615

1060 1015

2960 2930 2880 2600

* 1500 1455 1430 1375

  920 745 cm 1,920 745 cm (low) 1725

1230 1105 -

NMR spectrum (CD C 13)

9.46

8.34 7.92 7.67 7.59

7.53

  7,30 6,51 6,04 s IH s IH s IH d IH d IH d 1 H d 1 H s IH s IH 360 MHZ the base 3,58 3,47 2,82 2,77 2,59 1 , 14 0.95 0.87

in ppm.

  s RH s 1 H s 2 H s 3 H s 111 t 3 H t 3 H t 3 H

m almost s.

4.94 q l H 4.18 d IH 4.05 q 2 H

3.77 S 3 H

  center over'5.81 Mass spectrum of DCI isobutane

M + I + at 954

M + 14 + 1 to 968

M + 28 + I + to 982

  at 153 155 157 171 172 185 186 199

213 223 227 255 257 279 281 283 -

285,349 398,459 516,569,952,953 -

955 967 969 981 983.

  Calcd for C 56 H 68 N 6 O 08: 953.208

Example 3

  N- (O-4-deacetyl-4'-deoxyvinblastine-23-alkyl) ethyl isoleucinate. A solution of 0-4-desacetyl-4'-deoxyvinblastine

  hydrazide (0.6 g, 0.79 m N see US Patent 4,203,898 -

  column 24, line 51) in a mixture of 15 ml of methanol and 45 ml of 1N HCl is cooled to -7 ° C. 0.15 g of Na NO 2 are added to the solution and stirring is continued for 13 minutes at -70 ° C. C After addition of an aqueous solution

  saturated with NaHCO 3 until reaching a pH of 9, the solution

  obtained is extracted four times by CH 2 C 12 The combined organic phases are washed with a solution

  saturated with NaCl and dried over Mg SO 4.

  The solution is concentrated to a volume of 15 ml and ethyl isoleucinate (1.25 m N) is added thereto. The solvent is then evaporated off under reduced pressure. The residue is purified on a chromatography column.

  (If O 2.60 g) and eluted with ether CH 3 OH / NH 3 (96: 4).

  0.25 g of an amorphous product is obtained (yield Z).

  Mass Spectrum: (Isobutane Molec Ionization) 880 (M +), 894, 836, 849, 832, 445; 391, 355 cm-1

51 69 508 880 1

  Melting point 180-190 ° C = 104 (c O 154) -1 IR (CHCl 3) 3470, 2970, 1728, 1655, 1612, 1502 cm -1 UV (CH 3 H) 289, 268, 216 nm NMR (CDC) 13) 7.9 (NH), 654 and 6 06 H 9, H 12, 5.81 (H 14 -H 15) 4.60 (CHCO 2 (NH) 3.76 CO 2 CH 3, 3.58 CH 3-0, 3.33 and 2, E

  (H 3 A and H 3 B), 2.73 (N-CH 3), 0.69 (H-15 ').

2517680-

  Acute Toxicity Determination of LD 50 Acute toxicity of the compound of Example 2 N- (0-4-deacetyl-deoxy-4 'vinblastine-23-alkyl-0) triptophanate ethyl was studied in female NMRI mice Increasing doses of product are

  administered intravenously in one injection.

  The percentage of mortality is monitored as a function of time The LD 50 values obtained for the compound of Example 2 (deoxy V Trp E) and a reference product (deoxy vinblastine = LAV deoxy) are listed below: LD 50 Deoxy product VBL 20 Desoxy V Trp E (Ic) 91 5 The deoxy derivative V Trp E is therefore less toxic than the

reference compound.

  Antitumor activity The chemotherapeutic activity of deoxy sulfate sulfate V Trp E has been studied on leukaemias

lymphoblastic L 1210 and P 388.

251708 d

1 L 1210

  Female DBA 2 mice are inoculated with 10 leukemic cells Leproduit is administered intravenously the day after the transplant at a dose of 50 mg / kg Animal mortality is monitored

  as a function of time Table 1 shows the results

  obtained with the compound of Example 2 (1c).

  At the tested dose the derivative is more active than the LAV.

  This superiority has been confirmed in relation to the

deoxy LAV.

2 P 388

  Female DBA 2 mice receive intravenously 104 leukemic cells The products are administered i v the day after the transplant The animal mortality is monitored during

  The results are shown in Table 1.

  Deoxy V Trp E is significantly more active than the reference compound and has a very high percentage

long-term survivors.

Table 1.

Tumor

L 1210

  P 388 Percentage of Percentage of Product Dose Number STD ILS Surviving Survivors of Animals Day 30 Z Day 30 Day 60 VBL VBL Desoxy V Trp E Desoxy VBL Desoxy VBL Desoxy V Trp E, 4, 8 11.2, 6, 8 16.5 o 57.6 -21.6 -42 58.7 oooooo 73.3 o O. DBA 2 female mice are inoculated iv with 104 leukemia cells The products

  are administered i v at the doses and diagrams specified.

  MST median survival time jcur survival means

  They%% of increase in life span percentage increase in survival time.

ro u 1 oo o J Co

Claims (8)

As novel compounds, the derivatives of vinblastine having the following general formula II: (II) CR O in which R represents an amino acid ester, optionally protected, coupled to the vinblastinoyl-23 fragment by a link amide, the branched or unbranched ester group having from 2 to 9 carbon atoms, R represents a hydrogen atom or a hydroxyl group, R 2 represents a hydrogen atom, a formyl or acyl group comprising from 2 to 9 carbon atoms, carbon, R represents a hydrogen atom, a methyl group or a formyl group, with the exception of the case where R 5 represents a methyl group and R 1 represents an ehydroxyl group, as well as its addition salts with the mineral acids or organic. 2. Compounds of the general formula III. In which R 1 represents a hydroxyl group or a hydrogen atom, R 2 represents a hydrogen atom, an acyl or formyl group containing from 1 to 5 9 carbon atoms; R 3 represents independently, a hydrogen atom, a branched or unbranched alkyl group having 1 to 8 carbon atoms, a hydroxy group CI-C 8 alkyl, amino-hydroxy CI-C 8 alkyl , carboxy-C-C 8 alkyl, amido C 1 -C 8 alkyl, guanadino C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, thiol C 1 -C 8 alkyl cysteinyl methyl, thiomethyl-ethyl, benzyl, hydroxybenzyl> x Wherein R 3 represents, with the carbon atom to which it is attached and the nitrogen of the amide group, an azole or hydroxyazole ring; R 5 represents a hydrogen atom; hydrogen, a methyl group or a formyl group, and R 4 represents a linear or branched alkyl group having 1 to 8 carbon atoms, or a benzyl group, excluding the compounds o RI = t OH 3 and R 5 = CH 3, as well as their addition salts with mineral or organic acids.   Compounds according to claims 1 and 2,   characterized in that it is N (deacetyl-0-4 vin-   ethyl or methyl cristinoyl-23) -L-tryptophanate and its addition salts with pharmaceutically acceptable acids acceptable.   Compounds according to claims 1 and 2,   characterized in that it is N- (0-4 desacetyyl)   formyl vincristinoyl-23) -L-ethyl tryptophanate or   methyl and its addition salts with pharmaceutical acids acceptable.   Compounds according to claims 1 and 2,   characterized in that it is N- (0-4-deacetyl)   ethyl deoxy-vinblastinoyl-23-3) -L-tryptophanate, and its addition salts with pharmaceutically acceptable acids acceptable.   Compounds according to claims 1 to 5,   characterized in that they are 1: 1 addition salts with sulfuric acid.   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 any one of the Claims I to 6.   Pharmaceutical composition according to claim   cation 7, characterized in that it is in a form of administration in which the active ingredient is present at a unit dose of between about 2 and 900 mg.   Pharmaceutical composition according to Claim 7, characterized in that the active principle   is N- (4-deacetyl-O-4-vincristinoyl) -L-tryptopha-   ethyl nate, optionally in the form of an addition salt with a pharmaceutically acceptable acid. Pharmaceutical composition according to Claim 7, characterized in that the active principle   is N- (d 9 sacetyl-O4 desformyl vincristinoyl-23) -L-   ethyl tryptophanate, optionally in the form of a   addition salt with a pharmaceutically acceptable acid.   11 Pharmaceutical composition according to the invention   7, characterized in that the active ingredient is   N- (dgsacgtyl-O-4-dioxy-4 'vinblastinoyl-23 3) -L-   ethyl tryptophanate or the corresponding sulfate.