CS261339B1 - 7-Oxo-7H-benzo (c) fluorene derivatives and process for their preparation - Google Patents

Abstract

The solution relates to antineoplastically active derivatives of 7-oxo-7H-benzo(c)fluorene of the general formula I in which R denotes an amide-bound residue of acetic, palmitic, sorbic, benzoic, p-aminobenzoic, methanesulfonic and p-toluenesulfonic acids, as well as to a method of their production, consisting in the reaction of chlorides of the respective acids with a substance of the general formula III carried out in a chlorinated hydrocarbon environment and in the presence of pyridine at temperatures from 0 °C to the boiling point of the reaction mixture.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to antineoplastic active 7-oxo-7H-benzo (c) fluorene derivatives of formula (I).

och ₂ ch ₂ n.

( ^ch 3) wherein R is an amide bond of acetic, sorbic, palmitic, benzoic, p-aminobenzoic, methanesulfonic and p-toluenesulfonic acid, as well as a process for the preparation of said compounds.

Benzo (c) fluorene derivatives are known to carry various pharmacological activities, the most important of which are antitumor / Křepelka et al., Collection Czechoslovak Chem. Commun. 47, 1258 (1982), 47, 1857 (1982), Vancurova et al., Collection Czechoslovac Chem. Commun., 47, 1867 (1982), AO No. 212,669, U.S. Pat. No. 4,661,297, and interferonogenic activity (Smejkal et al., Acta virol. 29, 11 (1984)]. A significant antitumor effect is described in particular for 5- [2- (N, N-dimethylamino) ethoxy) ethoxy] -7-oxo-7H-benzo (c) fluorene hydrochloride, a compound of formula II,

HCI (11), which under the designation benfluorone is in the clinical trial phase and is being developed as a cytostatic for the treatment of human cancer. One potential metabolite of the compound of formula II is 5- [2- (N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene, the compound of formula III

_{OCH2 CH2 NHCH3} / 111 /

The compound of formula III shows a weaker antitumor effect compared to the compound of formula II, but is a valuable intermediate for the preparation of other benzo (c) fluorene derivatives including the preparation of compounds of formula I of the above-mentioned meaning R.

Compounds of formula I of the above-mentioned meaning of R have been tested for antitumor activity in animals with experimental transplantable tumors (HK-mammary adenocarcinoma, Kr 2 - Krebs ascitic tumor, B 16 - melanoma, STE - solid Ehrlich tumor,

Y-Yoshid's ascites tumor) when administered to experimental animals after ip, ip and sc. The measure of effectiveness was the prolongation of the survival of the experimental animals or the reduction of the tumor weight in the treated group compared to the control group. The cytotoxicity and cytostatic effect of the prepared compounds were also tested by the method of inhibiting the incorporation of labeled precursors into tumor cells in vitro. Yoshid's tumor cells were used for the experiments and the course of simultaneous incorporation of 5-iodo-2-deoxy- (6H) uridine and the mixture (U- ¹⁴ C) of amino acids was incubated at 37 ° C. IC50 values / mol ^{-1 -1} ) were determined from time dependence. For example, 5- [2- (N-acetyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene decreased at a dose of 50 mg / kg after a STE tumor weight of 17% and at a dose of 25 mg / kg. kg after prolonging the survival of animals with Y tumor by 23%. In Yoshida associous tumor cells (in vitro), he inhibited DNA biosynthesis (ICgg = 14 mol.l *) to a greater extent than proteosynthesis (IC, g = 36 mol.l ¹ ). Similarly, 5- [2- (N-methyl-N-palmitoylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene at a dose of 50 mg / kg after prolonged survival of animals with Kr 2 tumor by 14% and at 80 mg / kg ip reduced tumor weight by 21%. In the same range of about 20%, the weight of the STE tumor was reduced by ip application of 80 mg / kg of 5- [2- (N-sorboyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene.

5- [2- (N-benzoyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene at 80 mg / kg administered

Ip reduced the weight of STE by 20% and inhibited DNA biosynthesis (IC _g8 = 18 mol.l ^-1 ) and, to a lesser extent, proteosynthesis (IC ₅₎ = 261 mol.lbu of Yoshida ascites tumor cells.

To the same extent, the weight of the STE tumor at 80 mg / kg i.p.

5- [2- (N-aminobenzoyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene and 5- [2- (N-tosyl-N-methylamino) ethoxy] -7-oxo- 7H-benzo (c) fluorene. 5- [2- (N-mesyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene at a dose of 100 mg / kg after reducing HK tumor weight by 23% while prolonging survival by 20% and inhibited DNA biosynthesis (ΙΟ θ ^ = 5.9 mol.l ^- ''') and protein synthesis (ICJ-137 mol.l q ^{= 1)} in Yoshida ascites cells.

According to the invention, the compounds of the formula I having the above-mentioned meaning of R are prepared by reacting a compound of the formula III with 1 to 4 mol equivalents of the compounds of the formula IV,

R-Cl (IV) wherein R is acetyl, palmitoyl, sorboyl, benzoyl, p-aminobenzoyl, mesyl, p-tosyl, in a chlorinated aliphatic hydrocarbon, preferably dichloroethane, in the presence of 1 to 4 mol equivalents of a suitable base, preferably pyridine, at temperatures from 0 ° C to the boiling point of the reaction mixture.

Any of the methods used in organic chemistry to prepare acid amides, i.e., methods employing reactive acid derivatives and reacting them with amines, can be used to prepare compounds of Formula I as defined above. The use of compounds of the general formula IV with the above-mentioned meaning of R seems to be the most economically advantageous. Various basic non-reactive reagents of the formula IV, such as tertiary amines, heterocyclic bases, but also aqueous solutions of alkali hydroxides, can be used to bind the liberated hydrogen chloride in the reaction and carry out the reaction in a two-phase medium or in the presence of phase transfer catalysts. The use of pyridine and carrying out the reaction in a single-phase environment brings advantages in the ease of processing of the reaction mixture. After the reaction has been carried out, the reaction mixtures are worked up in the usual manner, for example by diluting the reaction mixture with water, separating the organic layer, concentrating it and purifying the crude product by crystallization or by silica gel column chromatography.

More detailed information on the preparation of the compounds of formula (I) of the above feature R will be apparent from the following non-limiting example.

Example

5- [2- (N-acetyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene

To a solution of 3 g (0.01 mol) of 5- (2- (N-methylamino) ethoxy) -7-oxo-7H-benzo (c) fluorene in 80 ml of dichloroethane was added 3 g (0.04 mol) of pyridine and 3.1 g (0.04 mol) of acetyl chloride were added dropwise with stirring, and the reaction mixture was stirred at room temperature for 5 h. After diluting the reaction mixture with 100 ml of water and shaking, the organic layer was dried over anhydrous sodium sulfate. Recrystallization of the crude material gave a melting point of 156-157 ° C (hexane).

The following were prepared in an analogous way:

5- [2- (N-methyl-N-palmitoylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene; m.p. 71-72 ° C (ethanol)

5- [2- (N-methyl-N-sorboylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene; m.p. 96-98 ° C (hexane)

5- [2- (N-benzoyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene; m.p. 132-135 ° C (hexane)

5- [2- (N-p-aminobenzoyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene; m.p. 194 až

196 ° C (hexane)

5- [2- (N-mesyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene m.p. 173-175 ° C (hexane)

5- [2- (N-methyl-N-p-toluenesulfonylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene; m.p. 201 to

204 ° C (hexane).

Claims (9)

OBJECT OF THE INVENTION wherein R is an amide bonded residue of acetic, sorbic, palmitic, benzoic, p-aminobenzoic, methanesulfonic and p-toluenesulfonic acid. 2. 5- / 2- (N-Acetyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) -fluorene 3. 5- / 2- (N-Methyl-N-palmitoylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene 4. 5- / 2- (N-Methyl-N-sorboylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene 5. 5- / 2- (N-Benzoyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene 6. 5- / 2- (N-p-Aminobenzoyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene 7. 5- [2- (N-Mesyl-N-methylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene 8. 5- / 2- (N-Methyl-N-p-toluenesulfonylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene 9. A process according to claim 1, which comprises reacting a compound of formula III with from 1 to 4 mol equivalents of a compound of formula IV. R - Cl (IV) wherein R represents an acetyl, sorboyl, palmitoyl, benzoyl, p-aminobenzoyl, mesyl, tosyl group, in a chlorinated aliphatic hydrocarbon, preferably dichloroethane, in the presence of 1 to 4 mol equivalents of a base, preferably pyridine, at temperatures from 0 ° C to the boiling point of the reaction mixture.