DE3245269A1 - N- (VINBLASTINOYL-23) DERIVATIVES OF AMINO ACIDS, THEIR PRODUCTION AND THERAPEUTIC APPLICATION - Google Patents

Description

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

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

Vinblastine-type bisindole alkaloids are well known compounds that form the carbon skeleton of the general formula

(D

own.

Examples of these compounds can be cited: Vxncaleukoblastin (U.S. Patent 3,097,137), leuurocristin or vincristine and leuosidine (U.S. Patent 3,250,220), vinglycinate (BE-PS 65 9 112) and Vindesin (BE-PS 813 168).

The latter compound is made by chemical modification of

natural vinblastine (I,

= OCH

= COCH ₃ ) / that through

Extraction from Catharanthus roseus leaves is obtained.

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

However, it has been found that these drugs have adverse side effects. Vincristine shows neurotoxic effects and vinblastine have high toxicity as far as hematopoietic Tissues are affected.

Their mechanism of action is similar to the mechanism that is used for the antimitotic effect of colchicine was established. These Drugs are likely to inhibit the polymerization of

BADORIQfNAL

3245289

Tubulin act to form microtubules and therefore cell division in the Inhibit metaphase.

The use of 1: 1 complexes of antitumoral toubiline bisindole alkaloids was described in BE-PS 854 05 3.

In some cases it will have lower toxicity and stronger chemotherapeutic activity than for the corresponding free alkaloids.

Other chemical modifications of vinblastine were tested. Vinglycinate sulfate (I, sulfate, R ^ = OCH ₃ ? R ₂ = COCH ₂ N (CH ₃ ) ₂ - Cancer Research 1967, 27_, 221-227) was also tested in clinical experiments, but it was found to be was generally not superior to vinblastine or vincristine.

BE-PS 813 168 discloses vindesine (I, R ₁ = NH ₂ , R ₂ = H) and other vinblastine C 1-4 carboxamide derivatives. Subsequent reports confirmed the therapeutic interest of vincjle ~ sin or 3-carboxamide-4-0-deacetyl-vinblastine, but this compound is apparently inactive for the treatment of murine 1210 leukemia in mice <CJBarnett et al., J. Med. Chem . 7A_, 88, 1978).

The new compounds described in the present invention are likely to substantially kill mice inoculated intravenously with P 388 and L 1210 leukemia, postpone.

The activities on experimental P 388 tumors are apparent Surprisingly superior to the Vinca alkaloids in question. Numerous complete decreases were observed.

The compounds of the present invention also show other important ones and unexpected advantages compared to vinblastine and known analogs, particularly vindesine.

O ■ £. HUL · U vJ

In particular, in general, the toxicity observed is / is less than the corresponding toxicity of vindesine or vincristine.

The new compounds according to the present invention correspond in detail of the general formula II

CH ₃ O

(II)

wherein R is an ester of an optionally protected <X-amino acid, bonded to the vinblastine-23-oyl moiety by an amide bond, the ester group, which can be straight-chain or branched, contains 2 to 9 carbon atoms and R- is a hydrogen atom or is a hydroxy group, R _{2 is} a hydrogen atom, a formyl group or a C ₂ -Cg-ACyl group, Rr is a hydrogen atom or a methyl group or a formyl group, with the proviso that compounds in which Rc is methyl and R _{1 is} a β-hydroxy group is, are excluded; or their addition salts with mineral or organic acids.

BATH ORIGINAL

32A5269

The following compounds are particularly preferred:

CO ₂ CH ₃

(III)

wherein R is a hydroxy group or a hydrogen atom, B ^e i ⁿ hydrogen atom, a formyl group or a ^C 2 ~ ^C 9 ~ acylphenylalanine is group, R each independently represents a hydrogen atom, straight or branched Cj-Cg-alkyl, hydroxy Cj-Cg-alkyl, aminohydroxy-C ^ -Cg-alkyl, carboxy-C ^ -Cg-alkyl, amido-C | -Cg-alkyl, guanadino-C - Cg-alkyl, amino-C - Cg-alkyl, thiol -Cj-Cg-alkyl, cysteinyl-methyl, methylthio-ethyl, benzyl-, hydroxy-benzyl, or a groupϊ

(IV)

or

(V)

or R ₃ together with the carbon atom to which it is attached and the nitrogen of the amido group forms an azole or a hydroxy-azole ring; R_ is a hydrogen atom or a methyl group or a formyl group, and R ^ is a straight-chain or branched C.-Cg-alkyl group or a benzyl group, with the proviso that compounds in which

at the same time R ₁ ß - OH and R _{5 are} -CH ₃ are excluded, -COOR _{4 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

R ₀ 0 1 3 n

-NH-GH-COR ₄

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

The compounds can be used as S-decarbomethoxy-O-'i-deacetylvinblastine-3-carboxamide are designated. However, they are preferably referred to as N- (vinblastine-23-oyl) -or N- (Vincristinoyl-23) derivatives of the following amino acids.

In particular, compounds preferred according to the invention of the general formula II are those in which R is hydrogen and the amino acid components are derived from one of the following amino acids: L- or D-tryptophan, leucine, "- iso leucine, valine, alanine or -Phenylalanine. Of these, L-tryptophan, L - isoleucine and L-alanine are of particular interest.

The present invention describes individual reaction products of amino acids with vincristine, 0-4-deacetyl-vincristine, Deformyl-O-4-deacetyl-vincristin and Deoxy-vinblästin B.

The latter compound can be obtained by hydrogenation of anhydrovinblastine which in turn can be obtained by dehydrating vinblastine or by coupling vindoline with catharantine

BATH ORIGINAL

66 *

- 11 is obtained (Potier et al., JACS 9 ^, 7017, (1976)).

The particularly preferred compound according to the present invention is ethyl N- (0-4-deacetyl-4'-deoxyvinblastine-23-oyl) tryptophanate.

If the amino acid contains functional groups in the side chain R ₃ (Formula III), such as lysine or cysteine, it may be necessary to protect the functional groups according to methods well known to Faqhraann.

Protection can be achieved depending on nature the group to be protected by condensation of a benzyl ^ t-butyl-, benzyloxycarbonyl- ^ t-butoxy-trifluoroacetyl-carbonyl- or trityl residues. Other well known protecting groups found in The peptide chemistry used can also be beneficial can be used.

The compounds of the present invention can be prepared in a customary manner starting from the corresponding vinblastine derivatives by hydrazolysis followed by nitrosation and reaction with the amino acid ester according to reaction sequence I obtained will.

NaNO

CH OH <-> I HCl OCOCH " ^J ^^^" V 0 ° C

OH COOCH ₃ HO '*' C-NH-IJH ₂

O amino acid ester

CH ₂ Cl ₂

HO C-N - & - CO-OR-

ο ^H

Reaction sequence I

The first step in this process is to add excess anhydrous hydrazine 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 ^e C. Particularly preferably, the temperature at about 60 ⁰ C is maintained.

The hydrazide of the bisindole derivative is then obtained by adding water, extracting with dichloromethane and concentrating isolated. The compound can be further purified by preparative chromatography (neutral silica); In the case of vincristine, the product obtained is 0,4-deacetyl-deformyl-vincristine-carboxhydrazide.

During the second stage, the hydrazide function of the modified vinblastine is converted into an acyl azide. These Transfer is carried out in a known manner by adding sodium nitrite to the dissolved hydrazide in a water-methanol-acid mixture.

The acid that is used can be hydrochloric acid,

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

The suitable acyl azide is preferably not isolated, but directly to the amino acid ester or optionally one protected derivative of the same dissolved in methylene chloride was added.

BATH ORIGINAL

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

The reaction mixture is maintained between about -3 ° C and +10 ⁰ C for 8 to 72 hours and generally for about 15 hours. Monitoring of the reaction is easily achieved by thin layer chromatography. After concentration, the compound of the formula II according to the invention can be converted into a sulfate acid or another salt derived from a mineral or organic acid by crystallization from a methanolic solution of the corresponding acid

The compounds according to the invention can by customary Chromatography and recrystallization techniques are purified.

If desired, the 4-O-deacetyl-vinblastine derivative obtained in this way can be reacylated, either directly to obtain the vinblastine derivative III, in which R _{2 is} COCH-- (J. Med. Chem. 22 , 391, 1979), or by preliminary formation of the 3,4-diacetoxy derivative followed by selective hydrolysis of the 3-acetoxy group at the 3-position. The hydroxyl group in C ₄ can usually be esterified by other activated acid derivatives which contain 2-9 carbon atoms. The O-4-formyl derivatives are obtained by formylation (formic acid-acetic anhydride) of the corresponding O-4-deacety compounds (see BE-PS 660 843).

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

In particular, the compounds of the invention are very effective valuable anti-tumor properties from being used in human therapy can be applied.

O L · H yJ £. U

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These amino acid derivatives can be used for the treatment of L 1210, P 388-type leukemia, gliomas, lymphosarcomas and other leukemias or malignant tumors. In human medicine, they can be used to treat Hodgkin ¹ see disease and for other solid tumors that can be treated with vinblastine, vincristine or vindesine. These compounds are also of value in veterinary medicine for treating tumors in animals.

Other interest therapeutic uses may be ngegeben for the new derivatives of the bis-indole alkaloids ^&. It has been described that vinblastine can be used in the treatment of certain forms of arthritis (US Pat. No. 4,208,411) and that vincristine can be used to treat psoriasis (US Pat. No. 3,749,784).

For their therapeutic use, the compounds according to the invention are, if appropriate, preferably in lyophilized form administered by the parenteral route, dissolved in a pharmaceutically acceptable solvent in the form of a base or 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 acids es al ze, or organic acid salts, such as acetic acid, propionic acid, succinic acid, tartaric acid, oxalic acid, Methanesulfonic acid and benzene sulfonic acid salts are preferred.

Physiological water (physiological saline solution) and other saline solutions that are buffered, for example with a phosphate, are suitable solvents. In general, can the compounds in human therapy in an analogous manner to the dex "technique and the limitations on the use of others Vinca-type alkaloids can be used.

BATH ORIGINAL

* «Β * t> ty

The active substance is generally employed at a posology varying between 0.01 mg to about 5 mg / kg depending on the derivative and the therapeutic regimen being used. The total weekly doses are in generally vary between 0.1 and about 35 mg / kg.

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

The compounds according to the invention can be used alone or in combination be used with other carcinostatic agents including, for example, the alkylating agents, the Antimetabolites such as methotrexate, 5-fluoro-uracil, 6-mercaptopurine, 6-thioguanine, the cystosine arabinosides, and antibiotics such as actinomycin D, daunorubicin, adriamycin and cis-diamino-dichloro-platinum. In particular, the new vinblastine derivatives can be used in combination with one another will.

The following specific examples illustrate, in a non-limiting manner, the process for obtaining the compounds according to the invention Links.

EXAMPLE 1

1. Production of 0-4-deacetyl-N-deformyl-vincristine-mono ~ hydrazide A.

958 mg of vincristine base are dissolved in a mixture of 10 ml of anhydrous hydrazine and 10 ml of methanol. The reaction mixture is kept at 60 ^° C. with stirring for 22 hours. The reaction mixture is then treated with water and then with water saturated with NaCl.

O £. H U L UO

The aqueous solution is extracted eight times with 15 ml of dichloromethane. The collected organic phases are treated with 20 ml of water, then 75 ml of water saturated with NaCl, and finally dried _{over Na 2} SO _4. After filtration and vacuum concentration, 900 mg of 0-4-deacetyl-vincristine-monohydrazide (purity over 90%) were obtained.

NMR spectrum (CDCl ₅ , 360 MHz)

9 _T 76 (s, IH), 8.37 (s, 1H), 8 _f 06 (-5.1H), 7 _f 53 (d, 1H), 7 _; 24 and7.07 (n, 3H), 6.82 (s, lH), 6.22 (s, l) _f 5 _f 87 (dd, lh), 5.67 (d, lH), 5 _f 43 ( s, 1H, 4 _f 03 (s, 1H), 3.94 (s, 3H), 3.86 (s, IH), 3.73 (s, 3H), 3.52 (s, 3H), 2 , 82 (s, 2H), 2.51 (S, IK),

0.93 (2t, 2 χ 3H)

Mass spectrum (electronic ionization bombardment)

154, 294, 355, 413, 524, 555, 695, 710, 723, 736, 739, 755 (M + 1) - 768, 769, 782 calculated for

^C 42 ^H 54 ^N 6 ° 7 ⁷⁵ -'942
2. Manufacture of the acid acide of 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 175.5 mg of sodium nitrite at 0 °} C. for 15 minutes.

The solution, kept at 0 ⁰ C and is then neutralized with NaHCO-z at 0 ⁰ C then extracted three times with dichloromethane. The collected organic phases are _{dried over Na p} SO | i, filtered and vacuum-concentrated without heating until a solution of about 10 ml is obtained.

^. Reaction with ethyl tryptophanate.

500 mg Äthyltryptophanat are then added with stirring at about 4 ⁰ C and the reaction checked by TLC. After 10 days, the reaction product is purified by chromatographic separation (40 g of silica gel 60, elution solution

■> BAD ORIGINAL

111 ·. ♦ ··.

- 17 -

medium ether / NH, -saturated methanol 96: 4 volume / volume). Fractions of 15 ml are collected by TLC be checked (thin layer chromatography). Unreacted amino acid is collected first (fraction 30 to 4o). The eluent is changed (ether / NH-z-saturated Methanol 86:14), and the converted derivatives are called 3 fractions collected; Fractions 44 and 45: 30 mg; Factions 46-53: 257 mg; Fractions 54-60: 115 mg).

The second part was ethyl N- (0,4-deacetyl-deformyl-vincristin-2j5-oyl) -tryptophanate Ia, which was homogeneous by TLC.

Mass spectrum : 984, 970, 956 (M ⁺ +1) 913, 912, 899 (DCJ isobutane), calculated for C55H66N609: 955.181.

UV spectrum (CH ₃ OH):

max: 282 (4 ^ 0) - 290 (4.18) - 322 (3.96) min: 254 - 287 - 305

IR spectrum _: (cm " ¹ ) _v

3400 - 2920 - 1720 - 1660 - 1610 - 1485 - 1450 - 1370 - 1345

1330 - 1290 - 1220 - 1165 - 1130 - 1025 - 1005 - 920 - 885 830-740

Nuclear Magnetic Resonance Spectrum (CDCl3,) 3 60 MH (ppm)

8.50 (s, IH)

8, 03 (s, 2H)

7 _r 77 (d, IH)

7.60 (d, IH)

7 _f 57 (d, IH)

6j95 (s, IH)

6.35 (s, IH)

5.89 (d.d., IH)

5, 78 (d, IH)

4 _r 75 (q, IH)

3.88 (s, 3H)

3, 67 (s, 3H)

l _f 23 (t, 3H)

O, 98 (t, 3H)

O.89 (t, 3H)

Fithyl-N- (0,4-deacetyl-vincristin-25-oy-l) -tryptophanate IB. The deformylated derivative I a (257 mg) is reformylated by using the method described in BE-PS 811,110.

The crude product thus obtained is separated by chromatography using a 20 cm column (silica gel, 30 g) and one after the other 3 eluents: ether / NEW-saturated MeOH 92: 8; 88: 12, 86: 14 cleaned. The discharge is collected as 15 ml fractions. The parliamentary groups 44-54 (^ 4.1 mg) contained the N-reformylated derivative Ib.

Mass spectrum (isobutane DCI): lOIL 997, 983 (M ⁺ +1), 970,

982, 996, 998, 999, 1012 calculated for C56H66N601.Q = 983.192

UV spectrum (CH ₃ OH) max: 270 (4 _f 18) - 290 (4 _f ll) plate 280 (4 ^ 12) shoulder (4.03)

BATH ORIGINAL

IR spectrum (KEr )

Bands at 3400 - 3040 - 2960 - 2920 - 2880 - 2850 - 1735 -

1725-1680 "- 1670-1665-1610-1490-1450-1225-745.

Example ₂

Ethyl-N - (0-4 deacetyl-deoxy - 4 ¹ - vinblastin-25-oyl-B) tryphtophanate Ic.

The 0-4-deacetyl-deoxy-vinblastinhydrazid is produced by the in US Pat. No. 4,205,898, column 24, line 51 et seq manufactured.

500 mg of the hydrazide in 12 ml of methanol are then treated _{with 57 ml of HCl IN and 104 mg of NaNO 2} ^{at 0} ° C. for 15 minutes.

The solution is then neutralized with NaHCO- * and extracted 6 times with 15 ml of dichloromethane. The organic phases are _{dried over Na 2} SOh and concentrated until a volume of about 10 ml is obtained.

The azide in solution is then brought into contact with Äthyltryptophanat (500 mg) at 4 ⁰ C with stirring. The reaction is checked by TLC (ether, MeOH). After 6 days the reaction is complete and the reaction product is purified by column chromatography over silica gel (18 cm, 50 g), eluting with 15 ml fractions.

The following eluents were used sequentially: Ether 96 NH, sat., MeOH 4 fractions 1-49 92 & parliamentary groups 50-57

86 14 parliamentary groups 71-90

Fractions 50-57 contain the desired reaction product Ic (108 mg).

BAD ORiGJNAL

- 20 -

The sulfate is produced by ether precipitation (2 # H ₂ SO ^ / ethanol).

UV spectrum of the sulfate (CH, 0H)

max: 224 (4.63) - 272 (4.32)
min: 247 (4, 03)
Shoulder: 286 (4.22) - 312 (3.72)

IR spectrum (KBr) of the sulfate.

342Ö - 3060 - 2960 - 2930 - 2880 - 2600 (weak) - 1725

1660 - 1615 - 1500 - 1455 - 1430 - 1375 - 1230 - 1105 -

1060-1015-920-745 cm " ¹ .

NMR-3 spectrum (CDCl ₃ ) 3 60 MHz of the base in ppm ,

9.46 SlH 7.53 d 1 H 4.34 g IH

8.34 SlH 7.30 d 1 H 4 _; 18 d IH

7.92 SiH 6.51 s 1 H 4 _; 05 q 2H

7.67 d 1 H 6. _f. 04 s 1 H 3.77 s 3H

7.59 d 1 H m. Centered around s. 5 81

BAD ORiGINAL

- 21 -

3.58 SRH

3.47 S IH

2.82 S 2Η

2.77 β 3Η

2 γ 59 S IH

1.14 t 3H

0.95 t 3H

0.87 t 3H

Mass spectrum of the base

DCI isobutane

M '+ 1 ⁺ beL954 M + 14 + l ^{+ part} 968 M + 28 + I ⁺ at 982

Ions at 153-155-157-171-172-185-186-199

213-223-227-255-. 257 - 279 - 281 - 2S3

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

955 - 967 - 969 - 981 -

for C ₅₆ H ₅₈ N ₆ O ₈ : 953.208

BAD ORaGfNAL

Example 3 Ethyl-N- (O-4-deacetyl-4'-deoxy-vinblastin-23-oyl-B) -

isoleucinate

A solution of O-4-deacetyl-4'-deoxyvinblastine-β-hydrazide (0.6 g, 0.79 mM - see U.S. Pat. No. 4,203,898, column 24, line 51) in a mixture of 15 ml of CH ^ OH and 45 ml of HCl 1N were cooled to -7 ⁰ C. NaNOp was added to the solution (0.15 ß) and stirring was continued for IJ minutes at -7 ⁰ C. After adding an aqueous saturated solution of NaHCO ,, until a pH value of 9 is reached, the resulting solution is extracted _{four times with CHoCl 2.} The combined organic phases were washed with saturated aqueous NaCl solution and dried over MgSO ^.

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 in a refrigerator for 4 days. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiOo, 60 g) and eluted with ether / CHgOH / NH ^ (96: 4). 0.25 g of amorphous product (yield 35 %) was thus obtained.

Mass spectrum : (Molecular ionization isobutane)

880 (M ⁺ ), 894, 836, 849, 832, 445; 391, 355 era " ¹

^C 51 ^H 69 ^N 5 ° 8 = ^ ⁸⁰ ' ¹ melting point 180-19O ⁰ C

a _D = 104 ° Cc = O _T 154)

IR (CHCl ₃ ) 3470, 2970, 1728, 1655 _r 1612, 1502 cm " ¹

UV

(CH ₃ OH) 289, 268, 216 nra

BATH ORIGINAL

NMR (CDCL ₅ ) 7 _r 9 (NH), 654 and 6.06 H ₉ , H ₁₂ , 5.81 (H ₁₄ -H ₁₅ ) 4 ^ 0 (CHCO ₂ (NH)) 3.76 CO ₂ CH ₃ , 3.58 CH ₃ -O, 3.33 and 2 _f 85 (H ₃ A and H ₃ B), 2.73 (N-CH ₃ ), 0.69 (H-15'J.

Acute toxicity determination of

The acute toxicity of the compound from Example 2: ethyl-N- (0-4-deacetyl-deoxy- ^J f ^l -vinblastine-25-oyl-B) -tryptophanate was determined on female NMRI mice. Increasing doses of the drug were injected intravenously in a single injection. The mortality percentage is determined as a function of time. The LDr "~ values for the

50

Compound (Deoxy-VTrpE) and a reference product: Deoxy-vinblastin (Deoxy-VBL) are given below.

Drug LDr -, - Deoxy-VBL 20 Deoxy VTrpE

(namely Ver.

bond Ic) 91.5

The Deoxy-VTrpE compound is as toxic as the reference compound.

Anti-tumor activity

The chemotherapeutic activity of the sulfate salt of Deoxy-VTrpE was applied to lymphoblastic leukemia L 1210 and P 388 studied.

1. L 1210

Female DBAp mice were inoculated with 10 leukemic cells. The product was administered by intravenous route, on the day after vaccination at a 50 mg / kg dose. The mortality of the animals is given as a function of time. The following table gives the results obtained

would do with the compound of Example 2 (Ic). At the dose tested, the compound is more active than vinblastine. This superiority was compared with Deoxy-vinblastin confirmed.

Female DBA ^ mice were injected intravenously with 10 leukemia cells inoculated. The products were i.v. administered on the day after inoculation. The mortality of the Animals is reported as a function of time. The results are shown in the table. Deoxy-VTrpE is clearly more active than the reference compound and indicates a higher percentage of surviving animals for a long time.

BATH ORIGINAL

TABEL

Tumor product dose number of
animals MST
20 days ILS percentage
the survival
living animals
at day 30 percentage
the survival
tying tie
re at
Day 6o 0 * *
A f L 1210 VBL 8th • ίο 10.4 57.6 0 O * ♦ · ·
* · · ·
* i VBL 19th 10 5.8 - 21 _f 6 0 0 * β
f «
FO> Deoxy VTrpE 50 10 11.2 70 0 0 I. ' * * »
ta *
* ♦ · P 388 VBL 4th 5 15.6 56 ' 0 0 u ΰ 4 Deoxy VBL 8th 5. 5.8 - 42 0 0 for St.
* *
BV * Deoxt VTrpE 30th ίο 16.5 58.7 0 0 40 15th 30th 191 67 53 50 15th 30th 191 87 73 _? 3 55 10 30th 212 80 60 60 10 30th 212 90 90

-4
Female D3Ap mice are inoculated with 10 leukemia cells via the iv-V / eg. The drugs

were indexed to the specified baddies via the IV route "

MST = mean survival time ILS % - 'ρ of increase in life span

NJ CO CD

Claims (14)

Dr. F. ZumsteJn sen. - Dr. E. Assmann - Dr. R. Koenigsberger Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun. PATENT LAWYERS APPROVED REPRESENTATIVES AT THE EUROPEAN PATENT OFFICE REPRESENTATIVES BEFORETHE EUROPEAN PATENT OFFICE 20 / Whether PATENT CLAIMS 1. Vinblastine derivatives of the general formula Γ ~ \ CO ₂ CH ₃ CH ₃ O wherein R is an ester of an optionally protected amino acid bonded to the vinblastine-23-oyl moiety by an amide bond / where the ester group, which can be straight or branched, contains 2 to 9 carbon atoms and R ^ is a hydrogen atom or a hydroxyl group, Ry is a hydrogen atom, a formyl group or a C ₂ ^- Cg-Acy! group, Rr is a hydrogen atom or a methyl group or a formyl group, with the proviso that compounds / in which at the same time R _{5 is} methyl and R | is a ß-hydroxy group, are excluded, · or their acid addition salts with mineral or organic acids. 2. Vinblastine derivatives of the general formula CO ₂ CH ₃ (III) 5 OH ? 3 - C - - NH - CH - C OR; wherein R _{1 is} a hydroxyl group or a hydrogen atom, R _{2 is} a hydrogen atom, a formyl group or a C ~ -C _Q acyl group, R-, each independently a hydrogen atom, straight-chain or branched C ₁ -Cg-alkyl, hydroxy-Cj- Cgalkyl, aminohydroxy-Cj-Cg-alkyl, carboxy-C ^ -Cg-alkyl, amido-Cj-Cg-alkyl, guanidino-Cj-Cg-alkyl, AmInO-C ₁ -Cg-alkyl, ThIoI-C ₁ -Cg -alkyl, cysteinyl-methyl, methylthio-ethyl, benzyl, hydroxy-benzyl, or a group: or (IV) CH - (V) or R ₃ together with the carbon atom to which it is attached and the nitrogen of the amido group forms an azole or a hydroxy-azole ring; R _{5 is} a hydrogen atom or a methyl group or a formyl group, and R _{4 is} a straight-chain or branched C ₁ -C 6 -alkyl or a benzy group, the simultaneous meanings of BATH ORIGINAL β ■ ft "3 - R ₁ is ß-OH and R ₅ is -CH _{3 are} excluded; or their acid addition salts with mineral or organic acid 3. Ethyl or methyl N- (0-4-deacetyl-vincristin-23-oyl) -L-tryptophanate or their addition salts with pharmaceutical acceptable acids. 4. Ethyl or methyl N- (O ^ -deacetyl-deformyl-vincristin ^ S-oyl) -L-tryptophanate or their addition salts with pharmaceutically acceptable acids. 5. Ethyl N- (O ^ -deacetyl-deoxyvinblastine-aa-β-oyl) -L-tryptophanate or its addition salts with pharmaceutically acceptable acids. 6. Compounds according to any one of claims 1 to 5, characterized characterized in that the addition salt is the 1: 1 addition salt with sulfuric acid. 7. Pharmaceutical composition for use in human or Veterinary medicine for the treatment of neoplastic diseases, containing one or more compounds according to one of claims 1 to 6. 8. A pharmaceutical composition according to claim 7 in an administration form, characterized in that the active Compound is contained in an amount of about 2 to 900 mg for a unit dose. 9. Pharmaceutical composition according to claim 7, characterized characterized in that the active compound is ethyl N- (0-4-deacetyl-vincristin-23-oyl) -L-tryptophanate or its addition salt with a pharmaceutically acceptable salt. J ϊί, H J 4. ü J - 4 - 10. A pharmaceutical composition according to claim 7, characterized in that the active compound ethyl-N- (O ^ - deacetyl-deformyl-vincristin- ^ S-oyl) -L-tryptophanate or is its addition salt with a pharmaceutically acceptable salt. 11. A pharmaceutical composition according to claim 7, characterized in that the active compound A "thyl-N- (0-4-deacetyl-deoxyvinblastine-23ß-oyl) -L-tryptpphanat or be Addition salt with a pharmaceutically acceptable salt. 12. Vinblastine derivatives, essentially as described in referring to any of the examples. 13. Pharmaceutical composition for use in human or Veterinary medicine, essentially as described with respect to any one of the examples. 14. A process for the preparation of a compound according to claim or 2 essentially as described with respect to any one of the examples. BAD ORIGfNAL