Connection with the structure of camptothecin, methods for their preparation, pharmaceutical compositions

 

(57) Abstract:

The invention relates to new alkaloids of the formula I

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present in various parts of Mappia foetida, and their pharmaceutical use and use them as the new synthons for preparing compounds with antitumor and antiviral activity, the same products are new synthons for new analogues of camptothecin and palidino. Also described is a method of obtaining compounds I. Special water-solubility of these new compounds is extremely important, as it allows you to enter them parenteral without becoming derivative. 5 S. and 2 C.p. f-crystals, 1 table.

The invention relates to alkaloid structure camptothecin isolated from Mappia foetida or received by polysyndeton of these alkaloids.

It is known that Mappia foetida, a plant growing in the Indian subcontinent, contains in its various parts, mainly in seeds, camptothecin, mapicon and palidin I and II (EP A-685481). In the "Journal of Medicinal Chemistry, 1979, vol. 22, N 3, describes derivatives of camptothecin and receive them.

The alkaloids of the invention have the following General formula I

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in which R represents and what about the metal, preferably sodium or potassium,1-C6-alkoxygroup, optionally substituted by fenoxaprop, amino, C1-C6-monoalkylamines or C2-C12-dialkylamino, in which the alkyl part is optionally substituted by amino groups, killingray; R2represents C2-C6is an alkyl group or a group of the formula COR3where R3represents alkyl, C1-C6or optionally substituted phenyl or benzyl.

Phenoxy, phenyl or benzyl groups may be substituted by halogen atoms; C1-C6-alkyl, C1-C6-alkoxy, nitro, cyano, C1-C3-halogenoalkane groups.

The compounds of formula I in which R represents hydrogen or methoxy, R1represents hydroxy or OM group (M = sodium or potassium) and R2represents acetyl, can be separated from Mappia foetida extraction artificially dried plant biomass at temperatures not higher than 50oC, preferably at 35oC, first aliphatic ketones or aliphatic esters and then aliphatic alcohols. In these working conditions 17-acetyl derivatives camptothecin and 9-methoxyamphetamine kisinga source camptothecin, these alkaloids have not been identified, due, probably, their decomposition to camptothecin during extraction with the use of improper solvents. In the presence of aliphatic alcohols these alkaloids easily turn into camptothecin even when the natural pH of the extraction.

This group of compounds can be obtained by selective acetylation of C17-hydroxyl camptothecin in an alkaline environment.

The resulting compounds can, in turn, be used as starting materials for producing other compounds of the formula I, in which R2differs from the acetyl and/or R1represents alkoxy, phenoxy or amino group, as defined above, or to obtain palidino I and II. For these purposes it is possible to use conventional methods of obtaining esters or amides, for example, the reaction of the compounds I, in which R1is the OM group, with alkylhalogenide, such as ethyl - or benzylbromide to obtain esters, or the reaction of compounds I, in which R1is HE with the amine and dicyclohexylcarbodiimide to obtain amides.

The connection I have cytotoxic activity against cell lines and tumors. For example the same line, resistant to most conventional chemotherapy (HCT116/VM46). The results proved that when the compound of the invention is more active than camptothecin.

The compounds I can, therefore, be used as an active start in anticancer pharmaceutical compositions in a mixture with suitable carriers, for example, injectable saline solutions. The dose can vary within wide limits (from 5 to 500 mg/day), but in principle they will be approximately 10 mg of alkaloid per day.

The following additional examples illustrate the invention.

Example 1

Selection 17-acetylanthracene and 17-acetyl-9-methoxy-camptothecin acids

3 kg of seeds Mappia foetida extracted three times with dry acetone (3 x 3 l) at room temperature. The combined extracts are concentrated to dryness to obtain 580 g of waxy mass, containing camptothecin, 9-methoxyamphetamine and a small number of 17-acetylanthracene acid. Plant material from the extraction with acetone again repeatedly extracted with methanol (3 x 3 l) at 10oC; after concentration of the extracts at low temperature get 200 g of dry residue, which was suspended in 1 l of water and e is the temperature not higher than 30oC. Gain of 28.9 g alkaloid fraction, enriched with a mixture of 17-acetylanthracene and 9-methoxy-17-acetylanthracene acids, and chromatographic in reversed phase through the column RP18, elwira a mixture of methanol/water and methanol to obtain three fractions, consisting respectively of kumararatne and camptothecin acids. This fraction cleanse advanced on silica gel, obtaining 3.8 g 17-acetylanthracene acid, having the following spectroscopic and chemical-physical characteristics: I. pl. 258oCD= +63,4 (=0,05, H2O);

1H-NMR (DMSO-d6) : 0.85 (t, 3H, H-18), 1.95 (m+s, 5H, H-19+COCH3), 5.20 (s, 2H, H-17), 5.40,60 (q, JAB= 10.6 Hz, H-5), 7.65-8.65 (m, 6H, arom).

Number 9-methoxy-17-acetylanthracene acid makes up one-fifth part of the previous number and it has the following physicochemical characteristics: I. pl. 208oCD= +is 56.4 (C = 0,05, H2O).

Example 2

Getting 17-acetylanthracene acid from camptothecin

1 g camptothecin suspended in 30 ml of water, add 340 mg of NaOH and incubated under stirring at 40oC for two hours or, in any case, to dissolve; the water is removed in vacuum and the residue is dissolved in 20 ml and stirring for about 2 hours. The solvent is removed in vacuum and the residue is distributed in a mixture of chloroform/methanol/water 5: 6:4. Phase methanol concentrated to dryness and the residue crystallized, receiving 17-acetylanthracene acid, having the same characteristics as the characteristics described in example 1.

Example 3

17-acetylcystein-21-methyl ether

17-Acetylanthracene (100 mg, 0.25 mmol) dissolved in dry DMF (8 ml) and to it add the dry potassium carbonate (68 mg, 0.49 mmol) and itmean (69 mg, 0.49 mmol), stirred at room temperature for 20 hours. The reaction mixture was filtered and washed with chloroform (5 ml). The filtrate is diluted with chloroform (10 ml) and washed with water (5 ml x 3). The organic phase is dried over dry sodium sulfate. After filtration the solvent is removed in vacuum and the residue (170 mg) is subjected to flash chromatography (CHCl3:CH3HE, 9:1). Specified in the header connection receive (45 mg, yield: 45%) as a solid.

1H NMR (CDCl3) : 1.02 (t, J=7 Hz, 3H, H-18), 2.09 (s, 3H, OCOCH3), 2.26-2.45 (m, 2H, H-19), 3.82 (s, 3H, OCH3), 5.38 (s, 2H, H-5), 5.52 (s, 2H, H-17), 7.51-8.42 (m, 6H, arom). MS (EI) M+422. So pl. (decomposition) 234-235oC.

Following the same method, but using ethylbromoacetate or tert-butylbromide (CDCl3) : 1.10 (t, J=7.5 Hz, 3H, H-18), 1.30 (t, J=7.5 Hz, 3H, CH3), 2.10 (s, 3H, OCOCH3), 2.30-2.55 (m, 2H, H-19), 4.25 (q, J=7.5 Hz, 2H, CH2), 4.70 (q, JAB= 15 Hz, 2H, OCOCH2CO), 5.32 (s, 2H, H-5), 5.52 (s, 2H, H-17), 7.6 (m, 5H, arom).

(b)1H NMR (CDCl3) : 1.10 (t, J= 7.5 Hz, 3H, H-18), 1.46 (s, N, (CH3)3), 2.10 (s, 3H, OCOCH3), 2.35-2.52 (m, 2H, H-19), 4.60 (q, JAB= 15 Hz, 2H, OCOCH2CO), 5.30 (s, 2H, H-5), 5.52 (s, 2H, H-17), 7.58-8.38 (m, 6H, arom).

Example 4

17-deacetylbaccatin acid, 21-ester

Compound b (60 mg, 0.11 mmol) dissolved in dry chloroform (2 ml). At 0oC in nitrogen atmosphere add attributively (33 mg, 0,17 mmol), stirring at 0oC for 1 hour and at room temperature for 1 hour. The reaction mixture was poured into 5% solution of NaHCO3(5 ml).

The aqueous phase is washed repeatedly with chloroform until then, until the chloroform phase was not colorless. The aqueous phase is neutralized with 2.5% HCl solution at 0oC to pH 7 and extracted with butanol (5 ml x 6). The butanol phase are combined and evaporated in vacuum, obtaining the remainder (51 mg), which is subjected to flash chromatography through silica gel, elwira a mixture of chloroform-methanol, getting mentioned in the title compound (11 mg).

1H NMR (DMSO-d6) : (ppm) 0.82 (t, J=7Hz, 3H, H-18), 2.12 (s+m, 5H, H-19 and H-17), 4.29 (f, J1 (f, C-18), 50.2 (f, C-5), 63.9 (f, C-5), 77.5 (s, C-20), 99.1 (d, C-14), 125.9 (s, C-16), 127.3 (d, C-10), 127.8 (s, C-8), 128.6 (d, C-9), 128.9 (d, C-12), 129.7 (s, C-6), 130.3 (d, C-11), 131.4 (d, C-7), 141.3 (s, C-3), 148.0 (s, C-13), 150.7 (s, C-15), 153.9 (s, C-2), 160.8 (s, 16a), 171.0 (s, 172.8 (s, C-21).

Basic research methods. Spectra1H-NMR and13C-NMR were obtained on a spectrometer Bruker AC 200 or Bruker AC 300; all values are given in M. D. (). HPLC analysis was performed on the chromatograph Merk Hitachi LC.A. These IR spectra were obtained on a FT/IR JASCO-300E. In cases where the required research in anhydrous environment, used a nitrogen atmosphere and solvents, fresh from CaH2or Na.

Camptothecin 21-Isopropylamine (4). Camptothecin (400 mg, 1.04 mmol) suspended in Isopropylamine (80 ml) under nitrogen atmosphere and was heated for 2 days at the boiling point under reflux to obtain a clear solution is orange. After evaporation of the solvent the crude product was purified flash chromatography (silica gel, CHCl3: CH3OH 95:5) to give compound 4 in the form of a solid yellow (457 mg, 98%).

1H-NMR(Py-d5) : 1.2-1.4 (9H), 2.55(dq, 1H), 2.75 (dq, 1H), 4.45 (m, 1H), 5.1 (s, 2H), 5.5 (d, 1H, J=8), 5.8 (d, 1H, J=8), 7.6 (t, 1H, J=5.3), and 7.8 (t, 1H, J=5.3), 7.95 (d, 1H, J=5.3), 8.05 (s, 1H), 8.20 (d+s, 2H), 8.35 (d, 1H, J=5.3).

13C-NMR (Py-(s), 132.463 (d), 133.609 (d) 145.170 (s), 150.262 (s), 154.638 (s), 157.126 (s), 164.053 (s), 175.149 (s).

IR (cm-1): 1667, 1650, 1511, 1458, 1405, 1240.

Camptothecin 17-acetyl-21-Isopropylamine (5).

To a solution of compound 1 (95 mg, 0.23 mmol) in CH2Cl2(5 ml) was added anhydrous pyridine (0,74 ml) and AU2On (0,73 ml). The reaction mixture was left overnight under conditions of mixing, at room temperature and nitrogen atmosphere. The mixture was washed with water and then 5% HCl and was extracted with CHCl3. After evaporation of the solvent the crude product was purified flash chromatography (silica gel, CHCl3: CH3HE 96: 4) to give compound 5 in the form of a solid yellow (95 mg, 92%).

1H-NMR (CDCl3) : 1.10-120 (9H), 2.15 (s, 3H), 2.30 (dq, 1H), 2.60 (dq, 1H), 4.04 (m, 1H), 4.85 (d, 1H, J=18.6), 5.10 (d, 1H, J=18.6), 5.30 (s, 1H), 5.40 (d, 1H, J=13.3), 5.55 (d, 1H, J=13.3), 6.9 (d, 1H), 7.20-7.90 (5H).

13C-NMR (CDCl3) : 7.816, 20.921, 22.273, 22.679, 33.125, 41.659, 50.236, 59.199, 78.681, 100.654, 125.088, 125.100, 127.528, 127.675, 127.824, 128.188, 129.319, 130.087, 130.474, 144.297, 148.457, 151.921, 161.567, 171.298 (x2).

N-Di-tert-butoxycarbonyl-1,4-diaminobutane (6).

To a solution of 1,4-diaminobutane (2 g, is 0.023 mol) and Et3N of 2.27 g, is 0.023 mol) in THF (35 ml) was added dropwise a solution of BOC2(2,47 g, 0,0113 mol) in THF (10 ml). The reaction mixture is stirred for 1 dedimania the filtrate evaporated in vacuum and the crude product is purified by chromatography (silica gel, CHCl3:CH3OH 9:1 and CHCl3:CH3HE: Isopropylamine 9:1:0,5) to obtain compound 6 in the form of oil (1,03 g).

1H-NMR (CDCl3) : 1.4 (9H), 1.5(m, 4H), 2.66 (t,2H, J=6), 3.09 (2H).

Camptothecin 21-N-di-tert-butoxycarbonyl-4-aminobutanoic(7)

To a suspension of camptothecin (250 mg, to 0.72 mmol) in dry pyridine (15 ml) add connection 6 (541 mg, is 2.88 mmol) under nitrogen atmosphere. The reaction mixture is heated to 80oC to obtain a clear solution yellow. After aging for three days at a temperature of 80oC cooled mixture is washed with 5% HCl, extracted with CHCl3and dried over Na2SO4. After evaporation of the solvent the crude product is purified flash chromatography (silica gel, CHCl3: CH3HE 95: 5) to give compound 7 in the form of a solid yellow color (224 mg, 58%).

1H-NMR (CDCl3+D2O) : 1.05 (t, 3H, J =7.4), 1.40 (9H), 1.59 (m, 4H), 2.20 (dq, 1H), 2.41 (dq, 1H), 3.15 (m, 2H), 3.35 (m, 2H), 4.85 (d, 1H, J= 12), 4.94 (d+s, 3H, J=12), 7.30 (t, 1H), 7.41 (t+s, 2H), 7.48 (d, 1H, J= 8.4), 7.61 (t, 1H, J=8.4), 7.82 (s. 1H), 7.95 (d, 1H, J=8.4).

13C-NMR (CDCl3) : 7.769, 26.543, 27.311, 28.211. 32.409, 38.962, 39.972, 49.817, 57.223, 78.771, 78.800 100.985, 127.278, 127.400, 127.892, 128.927, 129.049, 129.969, 130.191, 130.300, 142.961, 148.142, 151.689, 154.332, 155.966. 161.632, 173.011.

HPLC (RP8, 75%H2O, 25%CH3CN): 9,44 ur, when receiving the connection 5, compound 7 (94 mg, 0,17 mmol) is subjected to acetylation using AU2About (0.33 ml) and anhydrous pyridine (0,34 ml) to obtain compound 8 in the form of a solid yellow (81 mg 82%).

1H-NMR(CDCl3) : 1.10 (t, 3H, J=7.4), 1.40 (9H), 1.60 (m, 4H), 2.01 (s, 3H), 2.30 (dq, 1H), 2.50 (dq, 1H), 3.15 (t, 2H), 3.30-3.40 (m, 2H), 4.82 (d, 1H, J= 18.6). 5.05 (d, 1H, J=18.6), 5.40 (d+d, 2H, J=13.3), 7.20 (t, 1H), 7.32 (d, 1H, J=8), 7.40 (2H), 7.55 (t, 1H, J=8), 7.9 (2H).

13C-NMR (CDCl3) : 7.891, 20.885, 26.675, 27.499, 28.339, 32.964, 39.059, 40.151, 50.227, 58.800, 78.506, 79.031, 100.612, 124.778, 127.265, 127.691 (x2), 127.800, 128.988, 130.039, 130.406, 144.179, 148.146, 151.425, 155.950, 157.120, 161.530, 171.127, 172.126.

HPLC (RP8, 75%H2O, 25%CH3CN): 10,48 minutes

Camptothecin 17 acetyl-21-4-aminobutanoic triptorelin (9)

To a solution of compound 8 (30 mg, 0,052 mmol) in anhydrous CH2Cl2(2 ml) in nitrogen atmosphere at a temperature of 0oC added dropwise TFA (0.5 ml). The reaction mixture was stirred in nitrogen atmosphere at a temperature of 0oC for 1.5 h, then the solvent is evaporated in vacuum and the residue dissolved in CH3HE (to remove remaining F). After evaporation of the solvent in the re-deposition of CHCl3/CH3OH-petroleum ether get a connection 9 in the form of solid substances 5.4 (2H), 7.4-8.7 (6H).

Camptothecin 21-pyrrolidinone (10)

Camptothecin (200 mg, or 0.57 mmol) dissolved in pyrrolidine (30 ml) and heated for 2 days at a temperature of 70-80oC.

After evaporation of the solvent the residue is re-precipitated from CHCl3-petroleum ether and the crude product purified flash chromatography (silica gel, CHCl3: CH3HE 97:3) to give compound 10 as a solid (124 mg, 52%).

1H-NMR (CDCl3) : 1.05 (t, 3H, J=7.4), 1.80 (m, 4H), 2.35 (q, 2H, J= 7.4),3.05 (m, 1H), 3.19 (m, 1H), 3.60 (m, 1H), 3.65 (m, 1H), 3.86 (t, 1H, J= 5.3), 4.74 (d, 2H, J=5.3), 5.30 (s, 1H), 5.35 (s, 2H), 7.64 (t+s, 2H), 7.82 (t, 1H, J=8), 7.92 (d, 1H, J=8), 8.24 (d, 1H, J=8), 8.40 (s, 1H).

13C-NMR (CDCl3) : 7.656, 23.209, 26.470, 30.731, 47.323, 47.829, 49.924, 57.650, 77.183, 100.048, 125.500, 127.757, 128.068, 128.530, 129.487, 130.451, 130.600, 130.997, 143.644, 151.549, 162.068, 170.856.

HPLC (RP8, 75%H20, 25%CH3CN): 4,23 minutes

Camptothecin 21--ethyl ether-alaninate (11) and (12)

To a solution of hydrochloride--alanine ethyl ester (1.86 g, 12 mmol) in CH2Cl2(7 ml) at room temperature under nitrogen atmosphere add Et3N (of 6.7 ml, 48 mmol) and the reaction mixture is stirred for 2 hours. White precipitate is filtered off and the filtrate evaporated in vacuum (T<30C) obtaining a solution-alanine ethyl EF the atmosphere of nitrogen a solution-alanine ethyl ester in Et3N. the Reaction mixture is heated to 80oC to obtain a clear solution yellow. After three days of incubation at 80oC the cooled reaction mixture is washed with 5% HCl, extracted with CHCl3and dried over Na2SO4. After evaporation of the solvent the crude product is purified flash chromatography (silica gel, CHCl3: CH3HE first 97:3, then 95:5) to obtain the compound (11) (252 mg, 63%) and compound 12 (42 mg, 9.1 per cent) in the form of solids pale yellow color.

11:1H NMR (CDCl3) : 1.05 (t, 3H, J=7.4), 1.28 (t, 3H, J=8), 2.30 (dq, 1H), 2.40 (dq, 1H), 2.64 (t, 2H, J=5.3), 3.60 (dt, 2H, J=5.3), 4.18 (q, 2H, J=8) 4.90 (d, 2H, J=3.2), 4.98 (s, 2H), 7.5 (m, 3H), 7.70 (t, 1H, J=8), 7.85 (s, 1H), 8.04 (d, 1H, J=8).

*double peaks due to the presence of enol form amide.

12:1H-NMR (CDCl3) : 1.05 (t, 3H, J=7.4), 1.25 (t, 3H, J=8), 2.35 (dq, 1H), 2.45 (dq, 1H), 2.50 (m, 4H), 3.45 (m, 2H), 3.60 (m, 2H), 4.10 (q, 2H, J= 8), 4.30 (d, 1H, J=10.6), 4.95 (d, 1H, J=10.6), 5.10 (s, 2H), 6.72 (t, 1H), 7.40 (t, 1H), 7.55 (2H), 7.70 (2H), 8.05 (d, 1H, J=8), 8.15 (s, 1H).

HPLC (RP8, 75%H2O, 25%CH3CH): 2,80 minutes

Camptothecin 17-acetyl-21--ethyl ether-alaninate (13)

Using the same procedure as that for obtaining a compound 5, compound 11 (80 mg, 0.18 mmol) is subjected to acetylation using AU2On (0,32 ml) and anhydrous pyridine (0/SUB>+D2O) : 1.10 (t, 3H, J=7.4), 1.30 (t, 3H, J=8), 2.10 (s, 3H), 2.35 (m, 2H), 2.50 (m, 2H), 2.55 (t, 2H, J=5.3), 3.55 (m, 2H), 4.15 (q, 2H, J=8), 5.10 (d, 1H, J=18.6), 5.20 (d, 1H, J=18.6), 5.42 (d, 1H, J=10.6), 5.55 (d, 1H, J=10.6), 7.4-8.1 (6H).

HPLC (RP8, 75%H2O, 25%CH3CN): a 4.83 min

N-(2-cyanoethyl)-1,4-diaminobutane (14)

To 1,4-diaminobutane (26,4 g, 0.3 mol) in nitrogen atmosphere at a temperature of 0oC is added dropwise acetonitrile (15.9 g, 0.3 mol). The reaction mixture is stirred for 20-30 min at a temperature of 4-5oC, for 30 min at a temperature of 20-40oC and for 2 hours at a temperature of 100oC. the Product is purified by vacuum distillation to obtain compound 14 in the form of oil (so Kip. = 96-97oC, P = 6,610-2mbar, 17,5 g, 41%).

1H-NMR (CDCl3) : 1.1 (s, 2H), 15 (m, 4H), 2.5 (t, 2H, J=7.2), 2.6-2.7 (4H, J=7.2), 2.9 (t, 2H, J=7.2).

N,N-Di-tert-butoxycarbonyl-N-(2-cyanoethyl)-1,4-diaminobutane (15)

To a solution of compound 14 (5,16 g of 36.5 mmol) and Et3N (12.2 g, 120,6 mmol) in THF (30 ml) is added dropwise a solution of BOC2On (16.7 g, to 76.6 mmol) in THF (20 ml). The reaction mixture was stirred at room temperature during the day. White precipitate is filtered and the solid washed with THF several times. The combined filtrates evaporated in vacuum to obtain compound 15 in the form of oil (12,45 g, 100%).

Di-tert-butoxycarbonylamino (16)

To anhydrous ether (170 ml) at a temperature of 0oC carefully add LiAlH4(1.4 g, 36,3 mmol), then to a suspension of LiAlH4at a temperature of 0oC is added dropwise a solution of compound 15 (3.1 g, 9.08 mmol) in anhydrous ether (60 ml). The reaction mixture is stirred for 3 hours at a temperature of 0oC, then quenched by successive addition 4/5 ml of 1 N. NaOH and 15 ml of water at a temperature of 0oC. the Reaction mixture was filtered through a glass funnel. The combined filtrates are washed with saturated salt solution, the aqueous layer was extracted with CHCl3and dried over Na2SO4. The solvent is removed in vacuum, obtaining the connection 16 in the form of an oil (2.8 g, 98%).

1H-NMR (CDCl3) : 1.4 (18H+4H), 1.55 (2H), 2.6 (t, 2H), 3.0-3.2 (6H).

13C-NMR (CDCl3) : 25.49 (t) 27.20 (t), h.25 (q) 31.63 (t) 33.81 (t) 39.85 (t), h.31 (t), 78.80 (s) 79.16 (s), 155.50 (s), 155.86 (s).

Camptothecin 21-N2N3di-tert-butoxycarbonylmethylene (17)

To a suspension of camptothecin (700 mg, a 2.01 mmol) in anhydrous pyridine (50 ml) is added under nitrogen atmosphere, the compound 16 (2.8 g, 8.1 mmol). The reaction mixture is heated to 80oC to obtain a clear solution yellow. After vydergivanie and dried over Na2SO4. After evaporation of the solvent the crude product is purified flash chromatography (silica gel, CHCl3: CH3HE 96: 4) to give compound 17 in the form of a solid pale yellow color (730 mg, 52%).

1H-NMR(CDCl3) : 1.15 (t, 3H), 1.25 (4H), 1.45 (18H), 1.65 (2H), 2.39 (m, 2H), 3.1 (4H), 3.25 (m, 4H), 4.35 (d, 1H, J=13.2), 5.0 (d, 1H, J=13.2), 5.15 (2H), 7.5-8.2 (6H).

Camptothecin 17-acetyl-21-N2N3di-tert-butoxycarbonyl spermidine (18)

Using the same procedure as that for obtaining a compound 5, compound 17 (570 mg, 0.82 mmol) is subjected to acetylation using AU2On (1,54 ml) and anhydrous pyridine (1.65 ml) to obtain compound 18 in a solid yellow color (488 mg, 81%).

1H-NMR (CDC3) : 1.15 (t, 3H, J=6.9), 1.2 (6H), 1.45 (18H), 2.05 (s, 3H), 2.35 (m, 2H), 3.05 (4H), 3.2 (4H), 5.25 (s, 2H), 5.4 (2H), 7.5-8.4 (6H).

13C-NMR (CDCl3) : 7.87 (q), 20.97 (q), 25.66 (t), h.39 (t), h.37 (q) 32.93 (t) 40.15 (t), h.58 (t), 50.2 (t) 58.98 (t) 78.74 (s), 79.64 (s), 100.6 (d), 125.0 (s), 127.72 (d), 127.89 (d), h.35 (s), 129.32 (d), 130.19 (d), 130.61 (d), h.47 (s), h.45 (s), h.97 (s), 161.58 (s), h.15 (s).

HPLC (RP8; 75%H2O, 25%CH3CN): 18,47 minutes

Camptothecin 17-acetyl-21-spermidine di triptorelin (19)

Using the same procedure as for polycide yellow solid substance (505 mg, 99,7%).

1H - NMR (CDCl3+CD3OD) : 0.8 (t, 3H, J=6.5), 1.56 (4H), 1.73 (2H), 1.86 (s, 3H), 2.14 (m, 2H), 2.78 (m, 4H), 3.15 (2H), 5.03 (2H), 5.22 (2H), 7.4-8.3 (6H).

13C-NMR (CDCl3+CD3OD) : 7.15 (q) 20.19 (q), 22.52 (t), 23.74 (t), 25.82 (t), 31.73 (t) 35.53 (t) 38.31 (t) 44.93 (t); 46.73 (t), 50.0 (t), at 58.85 (t) 78.71 (s), 100.83 (d), 123.90 (s), 127.77 (d), 127.99 (d), h.39 (s), 128.54 (d), 130.53 (d), 131.54 (d), 144.20 (s), 148.04 (s), 151.89 (s), 156.25 (s), 161.68 (s), 171.74 (s), 174.89 (s).

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1. Connection with the structure of camptothecin General formula I

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in which R represents a hydrogen atom or a methoxy group;

R1represents hydroxy, C1- C6alkoxygroup, amino, C1- C6monoalkylamines or2- C12dialkylamino, in which the alkyl part is optionally substituted by amino groups;

R2is1- C6alkyl group or a group of the formula COR3where R3is1- C6alkyl, usloviia that R, R1and R2cannot simultaneously be H, NHCH(CH3)2, COCH3/COC5H11respectively.

2. Connection on p. 1, where R represents hydrogen or methoxy, R1is hydroxy, R2is acetyl.

3. Suede fact, that the extraction is carried out pre-dried plant biomass Mappia foetida at a temperature lower than the 50oC, aliphatic ketones and aliphatic esters and then aliphatic alcohols.

5. The method of obtaining compounds of formula I on p. 2, characterized in that conduct selective acetylation17-hydroxyl camptothecin in an alkaline environment.

6. The method of obtaining compounds of formula I on p. 1, characterized in that conduct the esterification of compounds on p. 3.

7. Pharmaceutical composition having antitumor activity, containing as active ingredient a compound according to PP.1 - 3 mixed with suitable carriers.

 

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