JPS58116491A - N-(vinblastinoyl-23) derivative of amino acid, manufacture and therapeutical use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to novel bisindole alkaloids.

More particularly, the present invention relates to conjugation products of amino acids and vinplasti/derivatives, processes for their preparation, their use as antitumor II agents, and pharmaceutical compositions containing them.

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

Bisindole alkaloids of the vinblastine type are well known compounds and have a carbon skeleton of the following general formula.

Examples of cholera compounds include vincaleuicoplasten (U.S. Pat. No. 3,027.737), airocrisde/or vincristine and leucdinone (U.S. Pat.
．． ．． 20j, No. 220), bi/gly7nate (Belgian patent no. The latter compound is obtained by chemical modification of natural vinblastine/(in formula l, R□=OCH,,R2=C0CH,'), and natural vinblastine is niteni+/(catharanthus-■I'u-).
) can be extracted from the leaves.

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

However, these drugs are known to have one undesirable effect. Pincristi/vinblastine has neurotoxic effects and vinblastine has high toxicity as far as hematopoietic tissue traps are concerned.

The mechanism of action of these substances is similar to that thought for the antimitotic trap of colchicine. These agents act through inhibition of tubule polymerization to form microtubules and later arrest cell division in metaphase traps.

Belgian Patent No. t3QL, 033 for the use of anti-tumor tubule-bisindole alkaloid l:/ complexes
listed in the number.

In some cases, they exhibit lower toxicity as well as effective chemotherapeutic activity than the corresponding free alkaloids.

Other chemical modifications of vinblastine have also been investigated. pinoglycinate sulfate (in formula I, R = OCH3, R
,= C0CH2N(CH,), and is a sulfate: Cancer *esearch /ri67.27
．． λ2/-227) tested in this clinical trial, but generally appears to be inferior to vinblastine or vincristine.

Belgian patent No. 1/3. No./6r discloses vindesine (Formula I, R=NH2: R2=H) and other vincilastene C8-carboxamide derivatives. The later report was about vindesine, or 3-karmeki? Mido μ-〇-deacetylbin plusden has been confirmed to be of therapeutic interest, but this compound has been found to be ineffective in the treatment of Ne/N/Co-10 leukemia inoculated with Kemax. (
C.J.

Barn@tt etc., J, M@d-Chken,,/ri7
1. ．． 2/, Zaza).

The novel compounds disclosed in the present invention are P31# and L/λ1
0 leukemia can substantially delay death in mice statically inoculated with leukemia.

Substantial p311! Activity against 'II tumors is surprising #1
was found to be superior to the control bi/kaalkaqid. A number of overall remission trends have been observed.

Additionally, the compounds of the present invention exhibit other important and unexpected advantages compared to vinblastine and the known analogue, vindecune.

To be more specific, I! The measured toxicity is generally lower than the corresponding toxicity of Vindesine or Pink 9Sten.

More specifically, the novel compounds of the present invention are as follows:
or their addition salts with inorganic or organic acids.

However, R is an ester group of an amino acid that may be protected and may be bonded to the vinblastine-23-oil component through an amide bond, and the ester group is a straight chain,
Any branched chain may be used, and R is a hydrogen atom or a hydroxyl group, and R2 is a hydrogen atom, a formyl hydrogen atom, a methyl group, or a forzyl group, and at the same time ~ is a methyl group, and R is β
- It cannot be a hydro-silicyl group.

A compound represented by the following formula or an addition salt thereof with an inorganic acid or an organic acid is preferred, R is a hydroxyl group or a hydrogen atom, and R
8 is a water atom, a formyl group, or an acyl group with a carbon atom number of λ~, and R3 is always independently a hydrogen atom, a linear or nine-branched alkyl group with a carbon atom number of l~g, a carbon atom number /
~1 hydroxyalkyl group, carbon atom/~♂ aminohydroxyalkyl group, carboxy-01-C8-alkyl group, amido-C-C8-alkyl group, guanasino Cel-C8-alkyl group, carbon s atom a/- aminoalkyl group, thiolalkyl group with carbon atoms/♂, 7steinyl-methyl group, methylthio-ether group,
Represents a pencil group, a dibenzyl group in a hydrocarbon group, or a group represented by the formula: % formula %, where R3 is co-trapped with the carbon atom to which it is bonded and the nitrogen atom of the amino group.
i Hydroxia! R5 is a hydrogen atom, a methyl group or a formyl group, R4 is a linear or branched alkyl group having carbon atoms/-4 or a benzyl group, and at the same time KR is β-OH and R
-000R4Fi Calgemeth 7 or Calgeethoxy is preferred. It represents an ester group derived from any of the isomers, and the naturally occurring ino acids are glycine, aranidi, and valine.

Leu7in, inleucine, serine, threonine.

American/42 formic/acid, Guk J i:/ rII, 7
x -454f N, Gourmet Ken/, Al4P N, Lysine, Cystine.

Cystine, methionine, phenylalanine/, thixin,
)! 77' Dooran, Nororin, Histenon.

'To'chu' / Ruri J 7 j or hydroxyl glolin.

These compounds may be named 3-7'calImethoxy7-Q-Hiro-rarchirupi/turasten-3-cal-quinamide. However, they are preferably named the 71-noic acid N-(vinplasten-.23-oyl)modi(tiN-(pincristenoyl-,23)lI44) and will be followed hereafter.

Among the compounds of the present invention having the general formula (2), a particularly preferred compound tiR2 is a compound in which hydrogen is hydrogen and the amino acid moiety is derived from /W1 of the following amino acid.

L- or Wortligtofa7. Among these amino acids, L-)su/topha''s L-ia
Of particular interest according to the invention are amino acids and vincristine, o-4t-de-7tylbi/cristene, deformyl-≠-deacetylbi/cristene and deoxy- A reaction product with vinblastine beta is provided.

These compounds can be obtained by hydrogenation of anhydrous vinblastine obtained by dehydration of vinblastine or by coupling vindoline with catharanthine (Potler et al., JAcs, /V7i 1.70/7).

0-≠-deacetyl-sin'-deoxypine plus de-23-oil)-tributophanate.

If the amino acid has a functional group such as lysine or cysteine in the even chain R (Formula I), it is necessary to protect the functional group according to methods well known in the art.

Depending on the nature of the group to be protected,
Dedel, penzyloxycarbonyl, t-butol? It can be achieved by condensing trifluoroacetyl cartilyl or trityl 1. Well-known title groups used in other begtide chemistry fields can also be used to advantage.

Compounds of the invention can be obtained from the corresponding vinprades/derivatives.
It can be prepared according to one known method by hydrazitrilysis followed by tntenitronation and reaction with an amino acid ester depending on the reactant ml.

H Reaction order! The first step in this process is to add excess anhydride and dorazine to the vinplastine solution in anhydrous methanol. This solution was kept in an inert atmosphere for 12 hours to 2 days for about 3
Heat at a temperature ranging from 0 to 70°C. Most preferably, the temperature is maintained near 60°C.

The hydrazide of the bisindole derivative is then isolated by adding water, extracting with dichloromethane and concentrating. This compound can later be purified by preparative amatodarafui (neutral silica). In the case of vincristine, the raw acid product obtained is O-≠-f acetyludeform ξ rubincristine cal-medium dihydrazide.

During the λ step, the hydranodo functionality of vinblastine is converted to an acyl azide. This conversion is accomplished according to the known method of adding sodium nitrite to dissolved human cells in a water-methanol-acidic mixture.

The acid used may be hydrochloric acid.

The reaction temperature is kept in the range 0-tC. After extraction with a water-immiscible neutral solvent, preferably methine/chloride, the organic phase is partially concentrated.

Acrylic acid is directly dissolved in methylene chloride without isolation.
I! It is preferable to add it to a decomposed amino acid ester or its preserved nine-conductor.

The amount of amino acids to be used is the modified Bimp 5Xf/cal
Approximately l to j equivalents of dP diazide.

The reaction mixture is aged at about -3 to loC for 72 hours, generally about /j hours. Monitoring of the reaction can be easily performed by thin layer chromatography. After concentration, the compounds of the invention of the formula can be converted to compounds derived from sulfur salts or other inorganic or organic acids by crystallization from methanolic solutions of the corresponding formula.

The compounds of the present invention can be purified by known chromatography and recrystallization methods.

If necessary, the thus obtained Hiro-0-deacetyl-vinblastine derivative can be directly reacylated to obtain a vinblastine derivative [where R2 is C0CH5 (J, Med,
Chem, /ri7ri, 2.2.35'/)] or 3. forming a q-diacetoxy derivative;
Reacetylation can then be achieved via a step of selectively hydrolyzing the 3-acetoxy group at the 3-position. The hydroxyl group at C in the μ position can be esterified with other activated acid derivatives having from 1 to 2 carbon atoms according to known methods.

Corresponds to 0-tIL-formyl derivative trap. - It can be obtained by phorification (formic acid-acetic anhydride) of a deacetyl compound (Belgian patent @++o,,
(See rtA3).

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

The compounds of the present invention exhibit extremely useful antitumor properties and can be used in human therapy.

These amino acid derivatives were added to L'210. It can be used for the treatment of Pjfr leukemia, sarcoma 9/14, as well as other leukemias or malignancies. h) (7
) medicine [in the treatment of h* di+) diseases and the use of vinblastine, vincristine or vindesi/
It can also be used for other solid tumors that can be treated with. These compounds are also useful in the veterinary field for the treatment of tumors in animals.

Other interesting therapeutic uses can be expected for the new derivatives of bisindole alkaloids. Vincristine can be used to treat certain types of arthritis (US Pat. No. 201.11-//) and vincristine can be used to treat psoriasis (US Pat. No. 3.71A, 7g≠ No.) has been reported.

For therapeutic use, the compounds of the invention, which may be in lyophilized form, are dissolved in a pharmaceutically acceptable solvent and administered by the parenteral route, either in basic form or in a pharmaceutically acceptable acidified form. It is preferable.

Among the acid addition salts, non-toxic and pharmaceutically acceptable salts, such as the inorganic acid salts of hydrochloric acid, phosphoric acid and sulfate, or acetic acid! Organic acid salts such as ropionic acid, succinic acid, tartaric acid, oxalic acid, methanesulfonic acid and benzenesulfo/acid acids are preferred.

For example, phosphate buffered saline as well as other salt solutions are suitable solvents. In general, the compounds of the invention can be used in human therapy in a manner similar to the uses and limitations for other alkaloids of the vinca type.

The active substances are generally distributed in dosages that vary from 0.0/ to about j to/9 depending on the derivative employed and the treatment schedule. /Total dosage per week is General K
Q, varies from / to about 3j to /IP.

The composition according to the invention is from 0.2! ; a compound of the invention may be prepared in an exposed dose of POOap alone or, for example, as an alkylating agent;
Methotrexate, j-fluoro-uracil, 6-merca/togerin, 6-thioguanine e Tonoyo 11 antagonistic substance: cistone arabinocyte and actinomycin yD
, daunorubicin, adriamycin and cis-diamino-dichloro◎-! It can be used in combination with other anticancer drugs containing antibiotics such as Latinx.

The following specific examples are illustrative, without limitation, of rounding methods to obtain compounds of the invention.

Example 1 / Preparation of o-4z-deacetyl-N-deformyl-vincristine monohydrazide 1 drop of vincristine base was mixed with anhydrous LP9 gin 1
Dissolve in a mixture of 0IIv and 10q of methanol.

The reaction mixture is maintained at 0.degree. C. for 1.2.2 hours with stirring. The reaction mixture is then treated with water followed by water saturated with NacA. The aqueous solution is extracted t times with ligLt dichloromethane. The combined organic phase was saturated with 20-J of water and further with NaC4.
jJ water and finally dried over Na, So.

P,! After drying under reduced pressure, 0-Hiro-deacetyl vincristine monohydrazide (M[7Q or higher)] of RiooW#9 was obtained.

NMR spectrum (coct3.3t OMH□):
9,7A(s, )H), g, 3
7(@ , /H) , fll) 4(s, jl
-1), 7.3'J (d%/H).

7. 2J & 7.07Crn, 3 days), 6. ♂, 2(s
, /H), Otsu, 2j (s, /H), 5 za 7 (
dd, /H).

5.67 (d, /H), j:4tj (s, /s).

tA03 (s, /H), 3-tap (s, jH),
3, ffA (s, /H), 3.73 (s, 3H).

3-6.2 (s, jH), QF, 2. (s, JH), Yu, j/(s % I H), 0.93 (2t, rice 3
英）izti, Kotasan, 3j! ,≠/3. jλ≠.

jjj, 6 ri, 710, 7 3.737. .

739.711(M+/), 71,1,';#'?
.

12 (042'54'607 Calculation for VC [7j Hirohiro 2) U Production of acid at of modified vincristine 110~vincristine monohuman 5+1 in λO-methanol
Thoroughly dissolve the bath solution t-63-/N) and treat with sodium nitrite of A and 77-j for OCK''C/j minutes.Then, the OcK-maintained solution t- OCK
Neutralize with CNaHCO3, then extract three times with dichloromethane. The combined organic phases are dried over Na, So, and concentrated in vacuo in one pass without heating until #l@ is about IO-.

3. Reaction with ethyltrit 7anate Next, 30011v of ethyltryptophanate was added at about 30°C with stirring and the reaction was analyzed by thin layer chromatography (TLC).
) to confirm.

After 10 days, the reaction product was purified by chromatographic separation (Hiroo O.
g of silica, eluent ether/NH8 saturated methanol (v/v).

/j- fractions are collected and checked by TLC.

First, collect unreacted amino acids (Iiii min 30~≠O)
Change the eluent (ether/NHs saturated methanol I
t, :/Hiro), react and divide the 90 conductor into three fractions, one of which is collected. Hirohiro Ryobu and ≠!, respectively. :30R9, fraction tI-
6~j3', 237■, fraction jhiro~1,0://389
It is.

The second portion was ether N-(0-!-deacetyl-r-formylvincristine-co-3-oil)-trit 7-anate I8, which was confirmed to be homogeneous by TLC.

Ms: 9g≠, 70. 74 (M”+/).

9/3.9/2. lr cotton (DCJ 4) butane) C5
5H66N6o9 ノcalculated value 2j j, /za/U V
(CH30H): max:, 2. ! f'-2(44,20)-2riOC
'1.1I)-3,2,2<3.76) IR(CIIL).

31700-2920-/720-jl, 60-jl,
10-/4tr! -/4AjO-/370-/3411
3-/330-/2PO-/220-//1sj-/1
30-10 no! -100! -ta, 20-r♂! -430
-717ON MR (CDCl3.31pOMHz)
CPlum): f, j (1) (s, /+), za',
O3Cm, JH), 777 (d, /H), 7 Otsu (1) (
d, /H), 7j7Cd, /H), AJ'j (i, /H
), t, 3j (Kyo, /+), Yoli (d, d,, /H)
, yo7f (d, /H), 1A7j (Q, /H), 3, l
rl (m, 3H), j, 47 (s, jl-1), /, J
j (t, 3 days), 0.7 Ir (t, jH), 0, l (
t, 3s) Oethyl N-(0-4!-r acetyl-vincristine-23-oyl)-tridetophane) III deformylated derivative 1-(coj7M9) in Belgian Patent No. Z//,/10-1! The crude product thus obtained using the method described in
0 rotation), continuous Kjfl elution life 1, immediate Chechyl/N1-1. Saturated methanol 5/2'', I'.

It is purified by chromatographic separation using 1rIr:/conirg:/lA. The effluent is collected as both parts of /jd. Both fractions≠≠~yoμ(j44/Wlg) contained the N-formylated derivative 1bli again.

MS (isobutane DCI): IQ/Hatadef.

9♂J(M”+/), ri70.Touko, ri9ot, ?Riza.

99ri, 10/2 Calculated value of C56H66N6010 -413, /riλuv
(CH30H): max 270(IA/g)-λ9(7(4(,//
) Flat λ♂θ (44/2) Shoulder (440j) IR (
niB ``) (儂).

3≠00-30hiro-294,0-2920-kotto
-2t! ;0-/73! -/72 to 1/610 -/1
,70-/l,l,j-/610-7tI-taO-lHiroshi10-/λλj-7Hiroyo Example -8)-Tritphanate Ic 0-μm7'7 cetyl-roxypine plus denhydrazide US Pat. No. V, 20! , Ely L
lly Co., column λ≠, line 57 et seq.).

The hydrazide of ΘoIIv dissolved in 12-methanol is treated with 37-NHCl and NI No. 2° with 10≠η for 13 minutes at 0°C.

The solution is then neutralized with NaHCO3 and extracted six times with lj-dichloromethane. The organic phase was Na25o,
Dry above and concentrate to volumetric IO-.

Next, the azide in the solution is brought into contact with ethyl tryptophanate (300H9) at Hiroo C. while stirring. The reaction is checked by TLC (ether, methanol). 6
After a few days, the reaction was completed and the reaction product was 7 liters (301
1) Purify with the above column (/rclIL) chromatography. Eluted as lj- fraction. The following eluents were used sequentially:

Ether 97. NH saturated methanol ≠: Both parts / ~ Hiro 9 pieces y:
so〜j7♂6 ノ≠=
77~ri0-minjO~j7 is the predetermined reaction product 1c
(101tw) Contained 5c. The sulfate salt is prepared by ether precipitation (2% H2SO4/ethanol).

u v (C)430) 1) Sulfate: max: j
λ<z (4+, Otsu3)-27,2(J, JJ)mln
: 2I1.7(lj03)7111 :
,2F4(4',,2J)-3/λ(3,7λ)+
R(nier, ca-') sulfate: 31120-301
．． 0-lj960-. 2も30-. 2ffO-, 2oto
o<weak)-t7.2! -1Atθ-16itar/! 00
-/ll-! ;3;-/ll-30-/373-/23
0-/103-10Q-10/j-Ta20-7≠YNMR(coct, , 340MH, ppm)
:9,≠A(s,/H), 7.13(d,/H), 4<
941-Cq, /H), r, j4t (s, /H).

7.30 (d, /H), IA/I (d,
/H),7,? 2(s, 7M), A, t/(s, /H)
.

@Qj (q, 214), 7. A7 (d, /H).

4.044 (s, /H), 3.77Cs, JH).

7. jri (d, / H), J:l centered on /? Spectrum of m''-s, j, jJ'(s, R+), 3
, lj7 (s, / H), 11 (S,, 2
H).

, 177 (s, j) 4), 2.3? (@, /H).

Otsulhiro (t, j+), O,ri J'' (t, 3H).

0, l7Ct, 3 days) MS (inobutane DIC) base: M+71rij4L, M+/Hiro+l+96? .

M+koJ’+/+ri♂λ.

Ion lj3-lj1-/7-/7/-/7.2-
113-/It, -/Tata, 2/3-223-. 2λ
7-λ! ! −λj7−27'? -21/-213-21
3;-311-9-391r-439-zit-1 Otsu?
-ta j2-ta j3-'? ! j-96 footer 6ter 9t/
-913 c,, +, 8N, o8 total 11. flL: ? ! 3.
201 Example 3 Ethyl N-(0-lA-deacetyl-V'-rO-Sebin Plasti y-23-Oil-e)-Inoloy7nate 0-IA-Deacetyl-≠'-Deoxypine Plasti/
-β-L Dracito (0,611,0,7 mM, US Patent No. ≠,) 03. ♂? (Refer to No. r, column λl, line 51)
lj-methanol and Hiroshi! The solution dissolved in the warm mixture of - and NHCj was cooled to -7C.

NaNO2(0,/!; 9) was added to the t# solution and stirring was continued for 73 min at -7 °C. After adding a saturated aqueous solution of NaHCO, until the pH is 7, the resulting 69 solution is extracted twice with CH2Cl2. The organic phases were combined and washed with a saturated aqueous solution of NaCl and dried over Mg5O.

The solution was concentrated to lj- and ethyl isoleucinate (/, 23 mM) was added. The reaction mixture's proboscis was left in a cold refrigerator for ≠ days. The solvent was evaporated under reduced pressure. The residue was eluted by column chromatography (N1-1s saturation) (6:≠). 0.23'li of amorphous product was thus obtained. Yield 3j-0 M$ (molecular ionized isobutane): Ir10Cv''), I'?+1-, I36.Itl'?
.

t3λ, Hiro≠3,391,336 CI! I engineering'59NB'8'''♂go,irnepm
: /10-/ri0℃(d). Two 10μ0 (c=
o, is≠) I R (CHCA,) clL.

3 Hiro 70. λri70. /7 pieces, /631. /1. /λ
.

ljOλ uv (OH, OH) nm: 2t, 24f, 16 NMR (CDCA, > ppm: 7ヂ(NH)
, A, j≠ and A, 0A(H,,' IJ! ) *
j t/ (814H Eng.).

5 4 o <cHco, CNH)>, 3. yt
(co□CM3).

j, jI (0M3-0), 3.33 and λlj(
H3A1H, 8λko, 7 j (N-CH,), 0.
6も(H-/j') Acute Toxicity-LD5゜ Measurement Example Compound of λ, namely ethyl N-(0-≠-racetyludeoxy-Hir'-bi/plasten-23-oil-
8) - Acute toxicity of trypto-7anate was determined in female NMRI mice. Increasing doses of drug were administered intravenously in a single injection.

Determine the mortality rate (S) as a function of time. Mark (14)
The LO values for K (7'oxy Vlpε) and the Shigo product, deoxy-vinplasten (deoxy vaL) K, were as follows.

0 Medicine LD.

Deoxy V8L 20 Accordingly, the compound Deoxy VTrpE is less toxic than the standard compound.

The anti-tumor activity of the sulfate salt of oxy-VTrpE is
The blastic leukemia L/colO and p31ft were investigated.

/, L/210 Female 01A mice were inoculated with /0' leukemia cells.

The product was administered by intravenous route 7 days after tissue implantation at a dose of jOη/9. Observe animal mortality as a function of time. Table 1 below shows the results obtained with the compound (Ic) of Example 1. At the doses tested, the compounds of the invention exhibit even higher activity than vinblastine. This superiority was confirmed by a comparison with Seabin Plus T.

, 2. p311 female DIA, mouse K/0' leukemia cells are inoculated intravenously. The products of the invention are administered intravenously one day after tissue transplantation. Animal mortality is observed as a function of time. The results are shown in Table 1. foxyVTrpE is more effective than standard compounds and has shown high rates of long-term subject survival.

13310 Gières, Belgium ・Liu Quacumbeenu 11

Claims (1)

[Claims] (1) General formula: However, R is an amino acid ester group which may be unprotected and may be bonded to the vinblastine-23-oil moiety through an amide bond, and may be a linear or branched The ester group, which may be a chain, contains from λ to ter carbon atoms, R1t
l is a hydrogen atom or a syl group in human c2, s*2 is a hydrogen atom, a holyl group, or an acyl group having a carbon number of λ~, and R8 is a hydrogen atom, a methyl group, or an expanded holyl group. However, at the same time K R, is a methyl group, and R is!
-It is not a hydroxyl group-. Pin Plus Derivatives or acid addition salts thereof with inorganic or organic acids. (2) General formula: where R is a hydroxyl group, 9 is a hydrogen atom, Ra is a hydrogen atom, a formyl group, or the number of carbon atoms λ
〜ri acyl group, R5 is always an independent pressure water lA atom,
Straight chain or branched alkyl group having 1 carbon atoms, hydroxyalkyl group having 7 to ♂ carbon atoms, carbon atom 11E
/~r 7-minohydroxyalkyl group, calgexy c
l~08-alkyl group, amido-01~C8-alkyl group, guanasinoCel08-alkyl group, aminoalkyl group with carbon atoms/-f, deolalkyl group with carbon atoms/~g, cysteinyl-methyl group, ethyltheoethyl group, benzyl, hydroxybenzyl, mataha, and R6 is a radical group that forms an azole or hydroxy-azole ring with the carbon atom to which it is bonded and the nitrogen of the amino group. , R4 is a straight-chain or branched alkyl group or benzyl group having carbon atoms/~l, and R5 is a straight-chain or branched alkyl group or a benzyl group having a carbon atom number/~l, and at the same time KR is on the β-side.
is never an ethyl group, the bottle shown by! cholera derivatives or addition salts of cholera with inorganic or organic acids. (3) Ether 9 is ethyl N-(0-Hiro-r aceterupincrisden 23-oil)-L-tritphanate or addition salts with pharmaceutically acceptable acids. (4) Ethyl or ethyl N-(0-≠-deacetyludeform Rubincristine-Jj-oil)-L-
) Ligdooranate or their addition salts with pharmaceutically acceptable acids. (5) Ether N-(0-Koichi deaceter-foxyvin!lasten-23-β-oil)-L-)ligdooranate or addition salts of this with a pharmaceutically acceptable acid. (6) The compound according to any one of claims (1) to (5), wherein the addition salt is a /:/ addition salt with sulfuric acid. (7) A pharmaceutical composition for use in human or veterinary medicine for the treatment of neoplastic diseases, containing one or more of the compounds described in any of claims (1) to (6). (8) A pharmaceutical composition according to claim 7 in dosage form, wherein the active compound is contained in an amount of about 2 to about 000 per unit dose. (9) The active compound is ether N-(〇-Hiro-deacederupincristen-23-oil)-L-tritphanate or its addition salt with a pharmaceutically acceptable acid. A pharmaceutical composition according to claim (7). 0I The active compound is ether N-(0-!-deacetyludeformylupincristen-23-oil)-
Claim No. 7, characterized in that it is L-tritphanate or its addition salt with a pharmaceutically acceptable acid.
) The pharmaceutical composition described in item 2. (b) The active compound is ethyl N-(0-goudeacetyl-deoxyvinblastine-23-β-oil)-
The pharmaceutical composition according to claim 7, which is L-tritphanate or an addition salt thereof with a pharmaceutically acceptable acid. (2) A conductor as described in substantially any of the embodiments. (2) A human or veterinary pharmaceutical composition substantially as described in any Example. (b) A method for producing a compound according to claim (1) or (2), which can be substantially described in any of the examples.