GB2111055A - M-(Vinblastinoyl-23) derivatives of amino acids - Google Patents

Abstract

Vinblastine derivatives of the general formula: <IMAGE> wherein R is an ester of an amino-acid which is possibly protected, attached to the vinblastin-23-oyl moiety by an amide bond, the ester group, which may be straight or branched, containing 2-9 carbon atoms and R1 is a hydrogen atom or a hydroxy group, R2 is a hydrogen atom, a formyl group or a C2-C9 acyl group, R5 is a hydrogen atom or a methyl group or a formyl group, with the provision that compounds where R5 is methyl and R1 is a beta -hydroxy group are excluded; or their addition salts with mineral or organic acids. The compounds are useful as drugs.

Description

SPECIFICATION N-(vinbiastinoyi-23) derivatives of amino acids The present invention relates to novel bisindole alkaloids. More particularly, the invention relates to combination products of amino acid with derivatives of vinblastine, to a method for their preparation, their use as antitumoral agents and to pharmaceutical compositions containing same.

These novel derivatives of vinblastine may be used in treating leukemia and malignant tumors in humans.

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

As examples of these compounds, one may cite : vincaleukoblastine (U.S. Patent 3,097,137), leurocristine or vincristine and leurosidine (U.S. Patent 3,205,220), vinglycinate (Belgian Patent 659,112) and vindesine (Belgian Patent 813,168). The latter compound is obtained by chemical modification of natural vinblastine (I, R1 = OCH3, R2 = COCH3), which is obtainable by extraction from Catharanthus roseus leaves.

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

However, these drugs have been shown to possess unfavorable side-effects. Vincristine shows neurotoxic effects and vinblastine, a high toxicity as far as hematopoetic tissues are concerned.

Their mechanism of action is similar to the mechanism which has been postulated for the antimitotic action of colchicine. These drugs would act through inhibition of the polymerisation of tubuline to give microtubules, and subsequent arrest of the cell division in the metaphase.

The utilization of 1:1 complexes of anti-tumoral tubiline-bisindole alkaloids has been described in Belgian Patent 854,053.

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

Other chemical modifications of vinblastine have been tested. Thus the vinglycinate sulphate (I, sulphate, R1 = LOCHS; R2 = COCH2N(CH3)2 - Cancer Research 1967,27,221-227), has also been tested in clinical experimentation but does not appear generally to be superior to vinblastine or to vincristine.

Belgian Patent number 813,168 disclose Vindesine (I, R1 = NH2, R2 = H) and other vinblastine C3 carboxamide derivatives. Subsequent reports confirmed the therapeutical interest of vindesine or 3-carboxamide 4-O-deacetyl vinblastine, but this compound appeared to be inactive for the treatment murine 1210 leukemia inoculated in mice (C.J. Barnett et al., J. Med. Chem. 21,88, 1978).

The new compounds described in the present invention are able to substantially delay the death of mice intravenously inoculated with P 388 and L 1210 leukemias.

Activities on experimental P 388 tumors have appeared, surprizingly, very superior to reference Vinca alkaloids. Numerous total remissions have been observed.

The compounds of the invention further show other important and unexpected advantages compared to vinblastine and known analogs, especially vindesine.

More particularly, the toxicity which has been observed is generally lower than the corresponding toxicity of vindesine or vincristine.

The new compounds of the present invention are more particularly those of the general formula 11:

wherein R is an ester of an a-amino acid which is possibly protected, attached to the vinblastin-23-oyl moiety by an amide bond, the ester group, which may be straight or branched, containing 2-9 carbon atoms and R1 is a hydrogen atom or a hydroxy group, R2 is a hydrogen atom, a formyl group or a CrC9 acyl group, F5 is a hydrogen atom or a methyl group or a formyl group, with the provision that compounds where F5 is methyl and R1 is a group hydroxy are excluded; or their addition salts with mineral or organic acids.

The following compounds are particularly preferred:

wherein R1 is a hydroxy group or a hydrogen atom, R2 is a hydrogen atom, a formyl group or a C2-C9 acyl group, R3, considered each time independantly, is a hydrogen atom, straight or branched C1-C8 alkyl, hydroxy-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, cysteinyl-methyl, methylthio-ethyl, benzyl, hydroxy-benzyl, or a group::

or F3 together with the carbon to which it is attached and the nitrogen of the amido-group, forms an azole or an hydroxy-azole ring; F5 is a hydrogen atom or a methyl group or a formyl group and R4 is a straight or branched C1-C8-alkyl, or a benzyl group, with the provision that compounds where, simultaneously, R1 is ss OH and F5 is -CH3 are excluded, -COOR4 is preferably the carboethoxy or the carbomethoxy group; or their addition salts with a mineral or organic acid.

In a preferred embodiment, the structural segment

in general formula III, represents an ester derived from any of the naturally-occuring amino acids and their optical isomers of D-configuration, namely glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, aspargine, glutamine, arginine, lysine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophane, proline, histidine hydroxy-lysine or hydroxy-proline.

The compounds may be designated as 3-decarbomethoxy-O-4-deacetyl vinblastine-3-carboxamide. They will however be preferably designated as N-(vinblastin-23-oyl) or N-(vincristinoyl-23) derivatives of amino-acids hereafter.

Particularly preferred compounds of the invention of general formula II are those wherein R2 is hydrogen and the amino acid moieties are derived from one of the following amino-acids: L or D tryptophan, leucine, isoleucine, valine, alanine or phenylalanine. Among these, L-tryptophane, L-isoleucine and L-alanine are particularly interesting.

The present invention describes more particularly reaction products of amino-acids with vincristine, 0-4-deacetyl vincristine, deformyl-O-4-deacetyl vincristine and deoxy-vinblastine B.

The latter compound may be obtained by hydrogenation of anhydrovinblastine obtained by dehydratation ofvinblastine or by coupling vindoline with catharantine (Potier et al, JACS 987017, (1976)).

Most particularly preferred compound of the present invention is ethyl N-(04-deacetyl-4'-deoxyvinblastin23-oyl)tryptophanate.

When the amino acid contains functional groups in the side chain F3 (formula Ill) such as lysine or cysteine it may be necessary to protect the functional groups according to methods well-known to those skilled in the art.

Protection may be achieved, depending on the nature of the group to be protected by condensing a benzyl, t-butyl, benzyloxycarbonyl, t-butoxy-trifluoroac6tyl carbonyl or trityl radical. Other well-known protecting groups in use in peptide chemistry may successfully be used.

The compounds of the present invention may be prepared in the conventional manner starting from corresponding derivatives of vinblastine, by hydrazinolysefollowed by nitrosation and reaction with the amino acid ester in accordance with the reaction sequence I

Reaction sequence I The first step of the process is to add anhydrous hydrazine in excess to a solution of vinblastine base in anhydrous methanol. The solution is heated in an inert atmosphere for 12 hours to 12 days at a temperature between about 30"C and 70"C. Most preferably the temperature is maintained around 60"C.

The hydrazide of the bis-indole derivative is then isolated by adding water, extracting with dichloromethane and concentrating. The compound may be later purified by preparative chromatography (neutral silica). In the case of vincristine, the product obtained is the 0,4-deacetyl-deformyl-vincristine carboxyhydrazide.

During the second step, the hydrazide function of the modified vinblastine is transformed into an acyl azide. This transformation is achieved in a known manner by adding sodium nitrite to the hydrazide dissolved in a water-methanol-acidic mixture.

The acid which is used may be hydrochloric acid.

The reaction temperature is maintained between 0 C and 5"C. After extraction with a water-immiscible aprotic solvent, preferably methylene chloride, the organic phase is partially concentrated.

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

The quantity of amino acid, to be used in about one to five equivalents of the modified vinblastine carboxazide.

The reaction mixture is maintained between about -3 and +10"C for 8 - 72 hours and generally for about 15 hours. Monitoring of the reaction is easily achieved by thin layer chromatography. After concentrating, the compound of the invention of formula II may be transformed into a sulphate 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 may be purified by conventional techniques of chromatography and re-crystallization.

If desired, the thus obtained 4-O-deacetyl vinblastine derivative can be reacylated either directly to give the vinblastine derivative Ill wherein R2 is COCH3 (J. Med. Chem. 22,391, 1979) orthrough the preliminary formation of the 3,4-diacetoxy derivative followed by a selective hydrolysis of the 3-acetoxy group in the position 3. The hydroxy group in C4 may be, in a conventional manner, esterified by other activated acid derivatives containing 2-9 C atoms. The 0-4 formyl derivatives are obtained byformylation (formic acid-acetic anhydrid) of the corresponding 0-4 deacetyl compounds (see Belgian Patent 660,843).

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

The compounds of this invention display particularly very useful antitumor properties which may be applied in human therapy.

The amino-acid derivatives may be used for the treatment of L 1210, P 388 type leukemia, gliomas, lymphosarcomas and other leukemias or malignant tumors. In human medicine they are used for the treatment of Hodgkin's disease and for other solid tumors treatable with vinblastine, vincristine or vindesine.

These compounds are also useful in veterinary medicine for the treatment of tumors of the animals.

Other interesting therapeutical uses may also be contemplated for the new derivatives of bisindole alkaloids. It has been described that vinblastine may be used for treating some forms of arthritis (U.S. Patent 4,208,411) and that vincristine may be used for treating psoriasis (U.S. Patent 3,749,784).

For their therapeutical use, the compounds of the invention, possibly in the lyophilized form, are preferably administered by parenteral route, dissolved in a pharmaceutically acceptable solvent, in the form of a base or of a pharmaceutically acceptable acid addition salt. Among the acid addition salts, the non-toxic and pharmaceutically acceptable salts, such as inorganic acid salts as hydrochloric acid, phosphoric acid and sulfuric acid salts or organic acid salts as acetic, propionic, succinic, tartric, oxalic, methansulfonic and benzene-sulfonic acid salts are preferred.

Physiological water and other saline solutions which have been buffered, for instance with a phosphate are appropriate solvents. In general, the compounds can be used in human therapy in an analogous manner to the technique and limitations in use for other alkaloids of the Vinca type.

The active substance is generally distributed at a posology varying between 0.01 mg to about 5 mg/kg depending upon the derivative and the therapeutic schedule whis is adopted. Total weekly doses will vary generally between 0.1 and about 35 mg/kg.

The composition in accordance with the invention are prepared as unitary doses of 2 to 900 mg.

The compounds of the invention may be used alone or in combination with other carcinostatic agents including, for example, the alkylating agents, the anti-metabolites such as methotrexate, 5-fluoro-uracil, 6mercaptopurine, 6-thioguanine, the cystosine arabinosides, and antibiotics such as actinomycine D, daunorubicine, adriamycine and cis-diamino-dichloro-platine. In particular, the new vinblastine derivatives may be used in combination.

The following specific examples illustrate in a non-limitative way the process for obtaining the compounds of the invention.

EXAMPLE 1 1. Préparation of O-4-deacetyl-N-deformyl-vincristine monohydrazide A 985 mg of vincristine base are dissolved in a mixture of 10 ml anhydrous hydrazine and 10 ml methanol.

The reaction mixture is maintained at 60"C, while stirring, for 22 hours. The reaction mixture is then treated with water and thereafter with water saturated by NaCI. The aqueous solution is extracted 8 times with 15 ml dichlorométhane. The collected organic phases are treated with 20 ml water, thereafter 25 ml water saturated by NaCI and finally dried on Na2 S04. After filtration and vacuum concentration, 900 mg of 0-4-deacetyl vincristine monohydrazide (purity over 90%) have been obtained.

NMRspectrum (CDC 13,360 MHz) 9.76 (s,1 H), 8.37 (s,1 H), 8.06 (s,1 H), 7.53 (d,1 H), 7.24 and 7.07 (m,3H), 6.82 (s,1 H), 6.22 (s,1), 5.87 (dd,1 h), 5.67 (d,1 H), 5.43 (s,1 H, 4.03 (s,1 H), 3.94 (s,3H), 3.86 (s,1 H), 3.73 (s,3H), 3.52 (s,3H), 2.82 (s,2H), 2.51 (s,1 H), 0.93 (2t, 2 x 3H) Mass Spectrum (electronic ionisation impact) 154, 294, 355, 413, 524, 555, 695, 710, 723, 736, 739, 755 (M+1)-768, 769, 782 calculated for C42H54N6O7 754,942 2.Preparation ofacid azid ofmodified vincristine A solution of 850 mg ofvincristine monohydrazide A in 20 ml methanol is treated with 63 ml HCI 1 N and 175.5 mg sodium nitrite for 15 minutes at OOC.

The solution maintained at 0 C is then neutralised by NaHCO3 at 0 C and thereafter extracted 3 times with dichloromethane. The collected organic phases are dryed on Na2SO4, filtrated and vacuum concentrated without heating until a solution of about 10 ml is obtained.

3. Reaction with ethyl tryptophanate.

300 mg of ethyl tryptophanate are then added while stirring at about 4 C and the reaction is checked by talc.

After 10 days, the reaction product is purified by chromatographic separation (40 g silicagel 60, elution solvent ether/NH3 saturated methanol 96:4 volume/volume). Fraction of 15 ml are collected which are checked by talc. The non-reacted amino-acid is first collected (fraction 30 to 40). The elution agent is changed (ether/N H3 saturated methanol 86:14) and the reacted derivatives are collected as three fractions: fractions 44 and 45:30 mg; fractions 46 - 53:257 mg; fraction 54 - 60:115 mg).

The second part was ethyl N-(0,4-deacetyl deformyl vincristine-23-oyl) tryptophanate la which was homogeneous by tlc.

Mass spectrum : 984,970,956 (M+ + 1) 913,912,899 (DCJ isobutane), calculated for C55H66N609 : 955,181.

Spectrum (CH30H): max : 282(4.20) -290(4.18) -322(3.96) min 254-287-305 1R spectrum: (cm-1) 3400-2920-1720-1660-1610-1485-1450-1370-13451330-1290-1220-1165-1130-1025-1005-920- 885830-740 NMR Spectrum (CDCl3) 360 MHz (ppm) 8.50 (s, 1H) 8.03 (s, 2H) 7.77 (d, 1 H) 7.60 (d, 1 H) 7.57 (d, 1H) 6.95(s, 1H) 6.35 (s, 1H) 5.89(d.d., 1H) 5.78 (d, 1H) 4.75 (q, 1 H) 3.88 (s, 3H) 3.67 (s, 3H) 1.23 (t,3H) 0.98 (t, 3H) 0.89 (t, 3H) Ethyl N-(0,4-déacetyl-vincristlne-23-oyl)-triptophanate 1B. The deformylated derivative la (257 mg) is re-formylated by applying the method described in Belgian Patent 811,110.

The raw product thus obtained is purified by chromatographic separation using a 20 cm column (silicagel, 30 g) and succesively 3 elution agents : ether/NH3 saturated MeOH 92:8 ; 88: 12,86: 14. The efluent is collected as 15 ml fractions. The fractions 44 - 54 (34.1 mg) contained the N-reformylated derivative Ib.

Mass spectrum (isobutane DCI): 1011, 997, 983 (M+ + 1), 970, 982, 996, 998, 999, 1012 calculated for C56H66N6010=983,192 UVspectrum (CH30H) max : 270(4.18)-290(4.11) plate 280 (4.12) shouldering (4.03) 1R spectrum(KBr) bands at 3400-3040-2960-2920-2880-2850-1735-1725-1680-1670-1665-1610-1490-1450-1225745.

EXAMPLE 2 Ethyl N-(0-4 deacetyl-deoxy-4'-vinblastine-23-oyl-B) tryphtophanate Ic.

The O-4-deacetyl-deoxy-vinblastine hydrazide is prepared by the method described in U.S. Patent 4,203,898 (assigned to Ely Lilly Co., column 24, line 51 and following).

500 mg of the hydrazide in 12 ml methanol are thereafter treated with 37 ml HCI 1 N and 104 mg NaNO2 for 15 minutes at 0 C.

The solution is thereafter neutralized by NaHCO3 and extracted six times with 15 ml dichloromethane. The organic phases are dryed on Na2SO4 and concentrated until a volume of about 10 ml is obtained.

The azide in solution is then brought into contact with ethyl tryptophanate (300 mg) at 4 C while stirring.

The reaction is checked by tic (ether, MeOH). After 6 days, the reaction is completed and the reaction product is purified by column chromatography on silicagel (18cm, 30 g), elution by 15 ml fractions.

The following elution agents have been successively used Ether 96 NH3sat,MeOH 4fractions 1-49 92 8 fractions 50-57 86 14 fractions 71-90 The fractions 50 - 57 contain the wanted reaction product Ic (108 mg).

The sulphate is prepared by ether precipitation (2 % H2SO4/ethanol.

Spectrum ofsulphate (CH30H) max : 224(4.63) - 272 (4.32) min : 247 (4.03) shouldering : 286(4,22)-312(3,72) IR spectrum {KBr) ofSulphate 3420-3060-260-2930-2880-2600(weak)-17251660-1615-1500-1455-1430-1375-1230-1105-1060- 1015-920-745 cm NMR spectrum (CDCI3) 360 MIIz of the base in ppm.

9.46s1H 7.53d1H 4.94q1H 8.34 s 1 H 7.30 d 1 H 4.18d1H 7.92s1H 6.51s1H 4.05q2H 7.67d1 H 6.04s1 H 3.77s3H 7.59 d 1 H m. about s. centered on 5.81 3.58 s RH 3.47s1H 2.82 s 2H 2.77s 3H 2.59 s 1H 1.14t 3H 0.95 t 3H 0.87 t 3H Mass spectrum ofthe base DCI isobutane M + 1+at954M + 14 + 1+at968 M + 28 + 1+ at 982 ions 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 calculated for C56 H65 N6 O8: 953,208 EXAMPLE 3 Ethyl N (-O-4-deacetyl-4'-deoxy-vinblastin-23-o yI-B)-isoleucinate A solution of O-4-deacetyl-4'-deoxyvinblastine p hydrazide (0,6g, 0,79 mM - see US patent 4203 898 column 24 line 51) in a mixture of 15 ml CH3OH and 45 ml HCI 1 N was cooled to -7 C. NaNO2 was added to the solution (0.15 g) and stirring was continued for 13 minutes at -7 C. After addition of an aqueous saturated solution of NaHCO3 till a pH-value of 9 is obtained, the resulting solution is extracted four times with CH2Cl2. The combined organic phases were washed with sat. aqueous NaCI solution and dried over MgSO4.

The solution was concentrated to a volume of 15 ml and ethyl isoleucinate (1.25 mM) was added. The reaction mixture was allowed to stand 4 days in a refrigerator. The solvent was the evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, 60g) and eluted with ether/CH3OH/NH3 (96:4) 0.25 g of amorphous product (yield 35 %) have been thus obtained.

Mass spectrum: (Molec.lonisation isobutane) 880 (M+), 894, 836, 849, 832, 445; 391,355 cm- C51H69N508 = 880.1 Melting point 180-190 C aD= 104 (c=0.154) IR (CHCl3) 3470,2970, 1728, 1655, 1612, 1502 cm-l UV (CH30H) 289,268,216 nm NMR (CDCl3) 7.9(NH), 654 and 6.06 H9, H12, 5,81 (H14-H15) 4.60 (CHCO2 (NH)) 3,76 CO2CH3, 3.58 CH3-O, 3.33 and 2.85 (H3A and H3B), 2.73 (N-CH3), 0.69 (H-15').

Acute toxicity-Determination of LD50 The acute toxicity of the compound of Example 2: ethyl N - (0-4-deacetyl-deoxy-4'-vinblastine-23-oyl-B) tryphtophanate has been determined on female NMRI mice. Increasing doses of the drug have been inoculated intravenously in a single injection. The mortality percentage is determined as a function of the time. The LD50 values for the above compound (deoxy VTrpE) and a reference product: deoxy-vinblastine (deoxy VBL) are indicated hereafter Drug LD50 DeoxyVBL 20 Deoxy VTrpE 91,5 (i.e. Compound Ic) The compound deoxy VTrpE is thus less toxic than the reference compound.

Antitumoral activity The chemiotherapeutic activity of the sulfate salt of deoxy VRrpE has been studied on the lymphoblastic leukemia L 1210 and P 388.

1. L 1210 Female DBA2 mice have been inoculated by 104 leukemic cells. The product is administered by intravenous route, the day after the graft at a 50mg/kg dose. The mortality of the animals is observed as a function of time. Table I hereafter indicates the results obtained with the compound of Example 2 (Ic). At the tested dose, the compound is more active than vinblastine. This superiority has been confirmed compared to deoxy-vinblastine.

2. P388 Female DBA2 mice are intravenously inoculated by 104 leukemic cells. The products are i.v. administered, the day after the graft. The mortality of the animals is observed as a function of time. Results appear in Table I. Deoxy VTrpE is clearly more active than the reference compound and indicates a higher percentage of surviving subjects at long term.

TABLE 1 Tumor Product Dose Number MST ILS Percentage of Percentage of of 30 days % surviving surviving subjects Animals subjects at at day 60 day 30 L1210 VBL 8 10 10.4 57.6 0 0 VBL 19 10 5.8 -21.6 0 0 Deoxy VTrpE 50 10 11.2 70 0 0 P388 VBL 4 5 15.6 56 0 0 Deoxy VBL 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 by l.v. route by 10-4 leukemic cells. The drugs are administrated byi.V.route at indicated doses.

MST=median survival time.

ILS=% ofincrease in life span.

It can be seen that the group R in the present vinblastines may be considered as representing the residue of an ester of an a-amino acid, which amino acid is optionally protected, the residue being linked via the a nitrogen atom and the alcohol part of the ester containing 1-8 carbon atoms.

The acyl group which R2 can represent is preferably an alkanoyl group.

The present compounds are particularly useful for treating neoplastic diseases.

Claims (19)

1. A compound which is a vinblastine of general formula:

ora salt thereof, wherein R represents an ester of an amino-acid which is optionally protected, attached to the vinblastin-23-oyl moiety by an amide bond, the ester group, which may be straight or branched, containing 2-9 carbon atoms; R1 represents a hydrogen atom or a hydroxy group; R2 represents a hydrogen atom, a formyl group or a C2-Cg acyl group; and F5 represents a hydrogen atom or a methyl group or a formyl group; with the proviso that F5 does not represent methyl while R1 represents hydroxy.

2. A compound which is a vinblastine of general formula:

or a saltthereof, wherein R1 represents a hydroxy group or a hydrogen atom; R2 represents a hydrogen atom, or a formyl group or a C2-Cg acyl group; R3 represents a hydrogen atom, straight or branched C1-C8 alkyl, hydroxy-C1-C5-alkyl, hydroxyamino-C1- C8-alkyl, carboxy-C1 -C9-alkyl, am ido-C1-C8-alkyl, g uan idino-C1-C8-alkyl, amino-C1-C8-alkyl, thiol-C1-C8-alkyl, cysteinyl-methyl, methylthioethyl, benzyl, hydroxybenzyl, or a group:

or R3 together with the carbon to which it is attached and the nitrogen of the amido group represents an azole or an hydroxy-azole ring; F5 represents a hydrogen atom or a methyl group or a formyl group; and R4 represents a straight or branched C1-C8-alkyl, or a benzyl group; with the proviso that F5 does not represent methyl while R1 represents hydroxy.

3. A compound according to claim 1 or 2 which is an addition salt of the vinblastine with a mineral or organic acid.

4. A compound according to claim 1 wherein the vinblastine is specifically named herein.

5. Ethyl or methyl N-(0-4-deacetyl-vincristin-23-oyl)-L-tryptophanate or an addition salt thereof with a pharmaceutically acceptable acid.

6. Ethyl or methyl N-(0-4-deacetyl-deformyl-vincristin-23-oyl)-L-tryptophanate or an addition salt thereof with a pharmaceutically acceptable acid.

7. Ethyl N-(O-4-deacetyl-deoxyvinblastin-23-p-oyl)-L4ryptophanate or an addition salt thereof with a pharmaceutically acceptable acid.

8. A compound according to any one of the preceding claims wherein the addition salt is the 1:1 addition salt with sulphuric acid.

9. A compound according to claim 1, which compound is substantially as described herein.

10. A compound which is a vinblastine derivative or a salt thereof, which derivative or salt thereof is substantially as described herein in any one of the Examples.

11. Pharmaceutical composition for use in human or veterinary medicine, which composition comprises a pharmaceutically acceptable carrier and one or more vinblastines or pharmaceutically acceptable salts thereof, which vinblastines and salts thereof are as claimed in any one of the preceding claims.

12. Composition according to claim 11 in unit dosage form, the unit dose containing 2-900 mg active compound.

13. Composition according to claim 11 or 12 containing as active compound ethyl N-(O-4-deacetyl- vincristin-23-oyl)-L-tryptophanate or an addition salt thereof with a pharmaceutically acceptable acid.

14. Composition according to claim 11 or 12 containing as active compound ethyl N-(O-4-deacetyl deformyl-vincristin-23-oyl)-L-tryptophanate or an addition salt thereof with a pharmaceutically acceptable acid.

15. Composition according to claim 11 or 12 containing as active compound ethyl N-(O-4-deacetyl- deoxyvinblastin-23ss-oyl)-L-tryptophanate or an addition salt thereof with a pharmaceutically acceptable acid.

16. Composition according to claim 11 substantially as described herein.

17. A compound for use in a method of treatment of the human or animal body by therapy, which compound is a vinblastine or a pharmaceutically acceptable salt thereof, which vinblastine or salt thereof is as claimed in any one of claims 1-10.

18. A process for the preparation of a compound claimed in any one of claims 1-10, which process is substantially as described herein.

19. A process for the preparation of a compound claimed in any one of claims 1-3, which process is substantially as described herein in any one of the Examples.