DE2260438C3 - Adriamycin esters and their salts, processes for their preparation and pharmaceuticals - Google Patents

Description

HO NJ γ Η

NH ₂ H
in which R has the following meanings:

Hydrogen, ethyl, n-propyl, n-heptyl, cyclopentylethyl, hydroxymethyl, aminomethyl, 2-carboxyethyl. Phenyl, benzyl, 2-hydroxynaphthyl- (1), pyridyl- (3), pyrrolyl- (2), ethoxy, amino,
and their salts with inorganic and organic acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that one 14-Bromdaunomycin or a salt thereof with a

ίο compound of the general formula MO — CO — R, wherein R has the meanings given in claim 1, and M is an alkali metal, alkaline earth metal or Ammonium ion or an alkyl substituted quaternary ammonium group means in one Reacts inert polar solvent and the product obtained in a manner known per se isolated and optionally converted into a salt.

3. Medicaments containing at least one of the compounds of claim 1 "in a mixture with a suitable carrier and, if necessary, customary pharmaceutical additives.

The invention relates to the subject matter specified in more detail by the claims.

The adriamycin esters according to the invention have a high anti-tumor activity and are the known adriamycin is therapeutically superior. This effect is made possible by the following Comparative tests proven.

The process according to the invention is carried out using an inert polar solvent such as Acetone, at the boiling point for a short period of time or in the cold for a longer period of time Response time carried out.

When the reaction is over. is the received Product isolated as such or converted into a salt of an inorganic or organic acid and purified by extraction and other purification processes.

The ED50 values of the compounds according to the invention and of adriamycin were determined in fibroblast cultures determined from mouse embryos, with some of the cultures infected with Moloney sarcoma viruses and a Part was not infected. After six days of treatment with the compounds to be investigated, the effective doses (ED50). The results of cytotoxic activity in the uninfected Cultures and the antiviral efficacy in the infected cultures are shown in Table I below summarized. The table also contains the values of the therapeutic index.

Table I.

links ED ₅₀ (y / mlt (c ylo toxic Therapeuti Effectiveness) shear index (antiviral 0.010 Effectiveness) 0.100 Adriamycin (reference substance) 0.0078 0.086 1.3 Adriamycin U-octanoate 0.0250 0.065 4.0 Adriamycin-H ^ nicotinate 0.0380 2.3 Adriamvcin ^ l4-propional 0.0260 2.5

The toxicity of the compounds according to the invention was determined by intravenous administration of the compounds according to the invention Determine connections to healthy mice. The LD50 values, determined over eight days of treatment, are summarized in Table II below. Adriamycin was used as a cattle subsidence.

Table II

links

LD ₅₀ mg / kß / day

Adriamycin (reference substance) 2.7

Adriamycin 14-octanoate 3.8

Adriamycin 14 benzoate 4.5

Adriamycin M nicotinate 4.0

Adriamycin 14-propionate 3.8

Adriamycin-14-phenyl acetate 4.0

CjH / He mice received an amount of 2.5x] Q <> Leukaemje tumor cells administered intravenously per mouse. The test animals were administered from the 1st to the 6th day then treated intravenously with the test compounds. The mean survival times and the number of Test animals still alive 60 days after treatment are shown in Table V below summarized

10 Table V

The anti-tumor activity of the compounds according to the invention was determined on a group of 10 mice (Swiss Cd-I) to which 1 × 106 tumor cells (Ascites Sarcoma 180) per test animal had been administered intrapentoneally. The test compounds were administered intraperitoneally to the test animals on the following day. The mean survival rate of the tested test animals in percent, based on the survival time of test animals to which no test compounds have been administered, are compiled in Table III below

25th

Table III

links

30th

control
Adriamycin

Adriamycin 14-benzoate

dose Medium
Survival
Time mg / k? (%) 100 0.5
1
2 166
206
233 0.5
1
2 201
287
266

35

40

Furthermore, the anti-tumor effect of the invention Compounds tested on mice (Swiss CD-I), which are either tumor tissue or neoplastic tissue Tissue (Solid Sarcoma 180) implanted subcutaneously. The test compounds were after 24 hours The doses of the test compounds were administered intravenously after the transplant for 8 days administered. The test animals were then sacrificed and the tumors removed and weighed. The tumor weight of the treated test animals was compared with that of the control animals. The weight gains, expressed as a percentage of the tumor weight of the control animals, are summarized in Table IV below.

Table IV

links dose Weight to took mg / kg (%) control 100 Adriamycin (comparison) 2.5 31.0 Adriamycin 14 octanoate 2.5 32.6 Adriamycin 14-benzoate 3.25 31.6 Adriamycin-14 nicotinate 2.5 37.9 Adriamycin 14 propionate 2.5 35.6

55

60

65

links dose Medium
Survival
Time number of
living
Animals after mg / kg Days 60 days control 10.2 0/10 Adriamycin (comparison) 1.5
2.5
4th 15.1
io, 8
toxic 0/10
0/10
0/10 Adriamycin 14 octanoate 2.5
3.25
4th 18.7
20.6
26.6 0/10
3/10
2/10

The following examples serve to further illustrate the invention.

example 1
Adriamycin 14 octanoate hydrochloride

3 g of 14-bromodunomycin hydrochloride are in 400 ml of anhydrous acetone suspended and 4.5 g of dried sodium octanoate are added. the The suspension is refluxed for 90 minutes, filtered and the solvent is evaporated off in vacuo. The residue is dissolved in 10 ml of methanol and with Treated 100 ml of chloroform. The solution is turned against Congo red with a methanolic hydrochloric acid solution acidified and then concentrated to about 50 ml, leaving a gelatinous precipitate of adriamycin 14-octanoate hydrochloride is obtained.

1.7 g of the product are obtained by crystallization from methanol-chloroform. M.p. 168-170 ⁰ C. [λ] Τ + 222 "(c = 0.05 methanol).

Example 2
Adriamycin 14-benzoate hydride

1 g of 14-bromdaunomycin hydrochloride is poured into 600 ml suspended in anhydrous acetone and treated with 3 g of dried sodium benzoate. The solution is 2 Refluxed with stirring for hours and evaporated the solvent in vacuo. To the 100 ml of water become residue. K) OmI chloroform and 2 g sodium bicarbonate added to the mixture is shaken for a long time and the whole thing is placed in a separating funnel. The layers are separated and the aqueous phase is extracted again with chloroform. The organic extracts are washed with water, concentrated to about 50 nil and countered with IN hydrochloric acid in methanol Congo red acidified. A semicrystalline precipitate of adriamycin-14-benzoate hydrochloride is produced obtain. Crystallization from methanol-chloroform gives 0.6 g of the product, F. 188-190 ° C, [a] IT + 224 ° (C = 0.15 methanol).

Example 3
Adriamycin 14 propionate hydrochloride

I g of 14-bromodunomycin hydrochloride is suspended in 65O ml of anhydrous acetone and 2 g of anhydrous sodium propionate are added. The suspension is refluxed with shaking for 1/2 hours, after which the solution is cooled, nitrated and evaporated in vacuo. The residue is dissolved in 50 ml of 0.1N hydrochloric acid and the solution is extracted twice with chloroform and five times with n-butyl alcohol until all of the colored product has passed into the organic layer. After concentrating the butanolic solution in vacuo, 0.620 g of crystalline, dark red colored adriamycin-14-propionate hydrochloride are obtained, mp 178-185 ° C., [/ x] f ° + 240 ° (c = 0.05 methanol).

Example! 4th
Adriamycin-14-phenyl acetate hydrochloride

20th

1 g of K-bromodunomycin hydrochloride is suspended in 600 ml of anhydrous acetone and treated with 3 g of anhydrous sodium phenyl acetate. The suspension is refluxed with shaking for 1 hour and then cooled, filtered and evaporated to dryness in vacuo. The residue is dissolved in 100 ml of 0.1N hydrochloric acid and the resulting solution is extracted twice with chloroform and then with n-butyl alcohol until all of the colored product has passed into the organic layer. The collected butanolic solutions are washed twice with a little water and, after the washing liquids have been separated off, concentrated in vacuo until crystallization. After standing, 14-phenylacetyl-adriamycin hydrochloride is collected as an orange-red, amorphous precipitate in the filter. The mixture is dried at 40 ° C. in vacuo. OJg of the product are obtained, mp 175-177 C, [λ] Ό " +220 '(c = 0.05 methanol).

Example 5
Adriamycin-H-nicotinate hydrochloride

1 g of 14-bromdaunomycin hydrochloride is suspended in 600 ml of anhydrous acetone and 3 g of dried potassium nicotinate are added. The suspension is refluxed with shaking for 2 hours, then cooled, filtered and evaporated to dryness in vacuo. The residue is treated with 100 ml of chloroform and 100 ml of an aqueous 2% sodium bicarbonate solution. The mixture is shaken well and the product is placed in a separatory funnel. The two layers are separated and the aqueous phase is extracted again with chloroform until all of the colored product is transferred to the organic phase. The collected chloroform extracts are washed with M'asser, concentrated to about 50 ml and acidified against Congo red with 1N hydrochloric acid in methanol. An amorphous precipitate of adriamycin-K nicotinate hydrochloride is obtained, which is collected through a filter and crystallized from methanol-chloroform. 0.5 g of the product are obtained, mp 180-182 ° C., [a] T + 212 ° (C = 0.05 methanol).

If you proceed as in the examples above described, but salts of other acids are used. the following adriamycin esters are obtained:

Adriamycin-14 formate,

Adriamycin-14-butyrate,

Adriamycin 14 glycolate,

Adriamycin-14-glycinate,

Adriamycin 14 hemisuccinate,

Adriamycin 14- (2'-hydroxynaphthoate),

Adriamycin-H-cyclopentylpropionate,

Adriamycin 14- (2'-pyrrole carboxylate).

Adriamycin M-carbamate and

Adriamycin-14-ethyl carbonal.

Claims (1)

Patent claims:
1. Adriamycin ester of the general formula O OH COCH ₂ OCR OH i H ₃ CO O OH