Method of producing derivatives of esters of 4-desacetylindole-dihydroindol alkaloids or salts there

专利摘要:
Compounds of the following formula are disclosed:… R - O - CO - X - CO - Z… wherein R is a dimeric indole-dihydroindole radical derived from a 4-acetoxy or 4-hydroxy antineoplastic dimer indoledihydroindole alkaloid, wherein Z is OR wherein R is the same or different, OH, OC1-3alkyl, NH2, NHNH2, an acylating group (Z<1>) or a carboxy protecting group (Z<2>), and wherein X is C1-4 straight chain alkylene, C2-8branched alkylene, C2-4alkenylene, C3-4alkynylene, C3-6cycloalkylene, phenylene, C1-4hydroxy substituted C1-4alkylene or a direct bond; and acid addition salts thereof. The compounds in which Z is OR, OH, OC1-3alkyl, NH2 or NHNH2 have utility as antitumor compounds and the remaining compounds are useful as intermediates in further synthesis.
公开号:SU1326196A3
申请号:SU843715348
申请日:1984-03-29
公开日:1987-07-23
发明作者:Джозеф Каллинан Джордж
申请人:Лилли Индастриз Лимитед (Фирма)；
IPC主号:

专利说明:


cm
one
The invention relates to a process for the preparation of new derivatives of bis-nn dolny alkaloids, namely, the derivative esters of A-deacetyl-indol dihydroindole-alkalloids of the common formuli
--Sh2-SI.
Qcox-co-: he
where R R R R R X Z
Z RI
COOCHj or COMj group; A CHj or -CHO group; HE;
CjHj;
- H;
a group -CHj-CHj-; HE,
or their salts possessing anti-X (evil properties.
The purpose of the invention is to obtain new derivatives of bis-indole alkaloids, which have pharmacological advantages over the natural bis-syndolate alkaloid, vinblastine.
The compound of the structure R-0-CO-CH -CH, -COOK, for example, is designated VLB-A-hemisuccinate, with the term "4-deacetyl" omitted, which is common to all radicals R.
Example 1. Getting VLB-4-β-hemisuccinate. 2 g of 4-desacetyl-VLB is dissolved in pyridine and 2 g of succinic anhydride is added to the resulting solution. The reaction mixture is stirred at ambient temperature for 5 hours. This reaction is also carried out in the temperature range of 0-50 ° C. The volatile components are removed by vacuum distillation and the residue is dissolved in methylene chloride. The methylene chloride layer is washed with 5% sodium bicarbonate solution, then with water. The organic layer is dried and the solvent is removed from it in vacuo.
Thus obtained VLV-4-hemisuccinate has the following physical properties:
1326196
IR spectrum: peaks at 1737, 1615, 1460, 1434 cm.
NMR spectrum (AHSC): 8.05; 7.54; 7.14; 6.58; 6.11; 5.83; 5.46; 5.28; 3.80; 3.78; 3.69; 3.62; 2.71; 0.92; 0.79 ppm
Sulfate is obtained by dissolving VLB-hemisuccinate in anhydrous ethanol and 2% ethanolic sulfuric acid solution, which is added to a pH of 3.95, followed by distillation of the volatile components. Sulfate has the following physical properties: (HjO) maximum at 214, 268, 283, 312 nm.
IR spectrum (KBG): peaks at 3400 (wide), 1740 cm.
Titration (66% DMF): pK 4.80; 6.10; 7.80. . .
The described procedure is used to obtain vincristine-4-hemisuccinate from 4-deacetylvincristine. Yield 700 mg (from 1.95 g).
The compound has the following physical properties:
IR spectrum: peaks at 1740, 1684 cm. NMR spectrum (CDCl1): 8.77; 8.15; 8.11; 7.72; 7.54; 7.18; 6.90; 6.83; 5.89; 5.39; 5.21; 4.69; 4.51; 3.86; 3.74; 3.67 ppm
Sulfate is obtained by adding a 2% solution of sulfuric acid in ethanol to an ethanol solution of the free base (400 mg). Exit 330 mg. R -0.16 (silica gel, methanol).
Vindesine-4-hemisuccinate is obtained from 300 mg of vindesine (4-deacetyl BLB 0-3 carboxamide). Yield 290 mg.
The compound has the following physical properties:
IR: peaks at 3450, 1733, 1693 cm. NMR (CDCl 3): 8.07; 7.52; 7.10; 6.54; 6.08; 5.92; 5.49; 5.27; 3.70; 3.59; 3.46; 2.83; 0.91; 0.78 ppm
Sulfate is prepared as described. From 200 mg of the free base, 160 mg of a white amorphous powder are obtained. TLC R.0.56 (silica gel, methanol).
4 Epidioxy VLB-4 hemisuccinate by
They are obtained from 4-deacetyl-4-zpoxy-VLB (1080 mg). Yield 540 mg. Rj :: 0.08 (SiOj, 1: 1 ethtacetate: methanol).
Vinblastic acid-4-hemisuccinate from 4-deacetyl-vinblastic acid has the following physical properties:
Rf-0.23 (SiO 1 sl, methanol),
IO-spectrum (CDCl1): 8.05; 7.52; 7.11; 6.57; 6.06; 5.71; 5.26; 5.14; 3.75; 3.60; 2.82; 0.90; 0.76 ppm
According to the described procedure, 4-desacetyl VLB is reacted with maleic anhydride in order to obtain VLB-4-hemimaleate.
The compound has the following physical properties:
IR spectrum: peaks at 1730, - 1590 cm
NMR spectrum (CHC1.J): 8.61; 8.04; 7.50; 6.59; 6.48; 5.78 (J 12H); 6.09; 5.7; 5.51; 5.3; 3.7.9; 2,70m d
According to the described method, VLB-4-hemiglutarate (700 mg from 3 g of the starting material) is obtained with the following physical properties:
IR spectrum: peaks at 3450, 1736 cm
NMR spectrum (CHCl1): 8.07; 7.53; 7.13; 6.53; 6.13; 5.83; 5.45; 5.24; 3.80; 3.68; 3.63; 2.69; 0.91; 0.81 ppm
, 25 (SiOj, 1: 1 ethyl acetate: methanol) sulfate (yield 50%).
, 08 (SiOj, 1: 1 ethyl acetate: methanol).
The proposed compounds are useful as antitumor compounds having activity against transplanted tumors in mice.
 In order to prove the value of the proposed compounds of the indicated formula, as mitotic inhibitors, their ability to cause a metaphase delay is determined by conventional methods.
Table 1 presents the results of the study.
Table 1




0.02
0.2
0.2
0.2
Concentration, µg / ml, indicating a metaphase delay:. 45
0.2
50
5g
Some of the presumed compounds also have activity against the transplanted tumors in mice.
The research results are summarized in Table 2, (P1534J stands for leukemia, and 6C3HED refers to lymphosarcoma).
table 2
Vindezin-4- - hemMsuccinate 6C3HED
VLB-4-hemisuccinate sulfate P1534J
6C3HED
Vincristine-4Hemisuccinate
sulphate P1534J
12 25 50
18 36
72 18 36 72
20 40
60 80
6C3HED 20 40 60 80
48
98
100
57
Toxic
ti
100 100
Toxic
63
83
94
96 100 100 100 100
From Table 2 it follows that the substances 5g have advantages over p of the known drug Vinka-Vinblast (VLB). From tests conducted on lymphosarcoma 6C3HED, it is clear that VLB is more toxic than the substances described. Thus, in this respect, the substances described have a significant advantage over VLB.
At a dose of 6 mg / kg, VLN results in 99% inhibition of tumors, but being toxic results in the death of three mice in a group of ten test animals. In another trial, at a dose of 3 mg / kg, VLB gives 40% mortality (4 out of 10) .- But at what dosages does VLB not provide 100% inhibition without death,
VLB 4-hemisuccinate at a dosage of 18 mg / kg does not lead to death from etching with 100% inhibition. Vindesine-4-hemisuccinate and vincristine-4-hemisuccinate are also non-toxic and provide 100% inhibition, respectively, at 50 and 20 mg. / kg

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the ester derivatives of 4-deacetylindol-dihydro- and (1-alkalloids of the general formula.
CHjO
2 1
where R is COOCH - or -CONH -group; A CHj or -CHO group; HE;
R, Ra 20
c, Hj;
25
R
Rf is H;
X - - the group-CHj-CHjZ - OH,
or their salts, characterized in that the compound is subjected to the interaction of the total
, 0
x
CH2
.
about
ROCOX-CO-Z,
where is r. Editor A. Shandor
Compiled by I. Fedoseeva
Tehred V. Kadar Proofreader M. Nozho
Order 3130/59 Circulation 371. Subscription VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
about
in an inert organic solvent at.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8308856|1983-03-30|

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