CS231207B1 - Quaternary salts of 572- (N, N-dimethylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene - Google Patents

Abstract

The subject of the invention are quaternary salts of the general formula I, in which R denotes an alkyl group with a straight chain of 1 to 8 carbon atoms or an allyl, propargyl or benzyl group and X a snail anion of chlorine, bromine or iodine and a method of their production, consisting in the quaternization of 5-/2-(N,N-dimethylamino)ethoxy/-7-oxo-7H-benzo/o/fluorene by the action of alkyl-alkenyl- or benzyl halides in an ethanol medium. The quaternary salts exhibit an inhibitory effect on the protein synthesis of tumor cells.

Description

MĚLKA MILAN MUDr. RNDr., HRADEC KRÁLOVÉ (54) Quaternary salts of 572- (N, N-dimethylamino) ethoxy / -7-oxo-7H-banzo / c / fluorene

The invention relates to quaternary salts of the general formula I,

in which R represents a straight-chain alkyl group having 1 to 8 carbon atoms or an allyl, propargyl or benzyl group and X is a chlorine, bromine or iodine anion and a process for the preparation thereof comprising 5- / 2- (N, N- dimethylamino) ethoxy (-7-oxo-7H-benzo) o-fluorene by treatment with alkyl-alkenyl or benzyl halides in ethanol. The quaternary salts show an inhibitory effect on the proteosynthesis of tumor cells.

The invention relates to quaternary salts of 5- [2- (N, N-dimethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene of formula (I),

Wherein ^X represents a straight-chain alkyl group having 1 to 8 carbon atoms or an allyl, propargyl or benzyl group and X represents an anion of chlorine, bromine or iodine, as well as a process for the preparation of said compounds.

It is known that 7-oxo-7H-benzo (c) fluorene derivatives carry different phermacological activities, depending on the position of substitution of the benzo (c) fluorene skeleton and the type of substitution. (See, eg, AO No. 212 669). The antitumor effect demonstrated in animals with experimental tumors and leukemias is considered to be a particularly important property. These effects excel especially in 5- [2- (N, N-dimethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene hydrochloride, the trade name Benfluron. Further details on biological effects are given in the author's certificate No. 212669.

Compounds of formula I wherein R and X are as defined above are quaternary salts of Benfluron. These compounds showed an inhibitory effect on tumor cell proteosynthesis, which is documented by ΙΟ ^ θ (concentration of the substance reducing the initial rate of substrate incorporation to 50%) rates of untreated controls) for some of the selected substances:

2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] ethyltrimethylammonium iodide, η 5> 10% aol / l,

2- / 5- (7-oxo-7H-benzo [c] fluorenyl) oxy] -ethyldimethylallylammonium bromide, ^{IC50 =} 4.5 * 10 5mel / l 2- / 5- (7-oxo-7H-benzo / c) fluorenyl ) oxy / -ethyldimethyloctylammonium bromide, 10. In vivo evaluation in experimental tumor animals revealed an inhibitory effect on tumor growth of HK, Sa 37, and Kr 2 by an average of 10 to 20%, depending on the doses used and the dosing regimen. When evaluated for in vitro antibacterial activity, 2- [5- (7-axa-7H-benzo [(c) fluorenyl) oxy] -ethyldimethylallylammonium bromide showed an antibacterial effect on Streptococcus beta haemolyticus and Staphylococcus pyogenes aureus at a minimum inhibitory concentration of 6.2). ml in nutrient medium.

The compounds of formula (I) as defined above for R and X are prepared according to the invention

XR (111) wherein R is as defined above and X is chlorine, bromine, or iodine, in an inert medium, preferably ethanol, at temperatures ranging from 20 ° C to the boiling point of the reaction mixture.

The compound of formula (II) is prepared according to FIG. Certificate No. 212 669.

After completion of the reaction, the reaction mixtures are worked up by obligatory methods for these types of reactions; for example, after cooling the reaction mixture, the precipitated substances are suctioned off and purified by crystallisation, or the reaction mixtures are concentrated to dryness and the crude product is purified by silica gel column chromatography.

More detailed information on the preparation of the compounds of formula (1), with the meanings given above for R and X, will be apparent from the following non-limiting examples.

Example 1

2- [5- (7-Oxo-7H-benzo [c] fluorenyl) oxy] ethyltrimethylammonium iodide To a solution of 159 mg (0.5 nunol) of 5- [2- (dimethylamino) ethoxy] -7-oxo-7H- of benzo (c) fluorene in ml of ethanol was added 70.5 mg (0.5 mmol) of methyl iodide and allowed to stand at 20-25 ° C for 24 hours. During the reaction time, a precipitate forms and is filtered off with suction. Recrystallization from methanol gave a melting point of 255-257 ° C.

The following were prepared in an analogous way:

2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] ethyldimethylpropargylammonium bromide, m.p. 175 DEG-177 DEG C. (chloroform-hexsn)

2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] -ethyldiaethylallylH-nitro-bromide, m.p. 225 DEG-227 DEG C. (chloroform-ethanol).

Example 2

2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] -ethyldimethyloctylammonium bromide

To a solution of 5- (2- (dimethylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene (159 mg, 0.5 mmol) in ethanol (2 mL) was added N-octyl bromide (193 mg, 1 mmol) and reaction mixture. reflux for 8 hours,

After completion of the reaction, the reaction mixture was evaporated to dryness, the residue was dissolved in chloroform and purified by silica gel column chromatography using chloroform as eluent. Combined fractions and crystallization from benzene-hexane gave a melting point of 201-203 ° C.

The following were prepared in an analogous manner:

2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] ethyldimethylpropylammonium bromide, m.p. 251 DEG-253 DEG C. (ethanol)

2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] ethyldimethylbenzylammonium chloride, m.p. 147 DEG-149 DEG C. (ethanol-benzene).

SUBJECT OF THE INVENTION

Claims (8)

SUBJECT OF THE INVENTION 1. Quaternary salts of formula I, 5- / 2 - (. N, N-dimethylamino) ethoxy / 7-oxo-7H-benzo / c / of the fluorene © X ^CH 3 OCH ₂ CH ₂ N <- CH ₃ R R / 1 / in which R represents a straight-chain alkyl group having 1 to 8 carbon atoms or an allyl, propargyl or benzyl group; and X represents an anion of chlorine, bromine or iodine. 2. 2- [5- (7-Oxo-7H-benzo [o] fluorenyl) oxy] ethyltrimethylammonium iodide. 3-2- [5- (7-oxo-7H-benzo [c] fluorenyl) oxy] -ethyldimethylpropargylammonium bromide. v t 231207 4 4. 2- [5- (7-Oxo-7H-benzo [c] fluorenyl) oxy] ethyldimethylallylammonium bromide. 5. 2- [5- (7-Oxo-7H-benzo [c] fluorenyl) oxy] ethyldimethyloctylammonium bromide. 6. 2- / 5- (7-exe-7H-benzo [c] fluorenyl) exyl-ethylmethylprepylemenium bromide. 7. 2- [5- (7-Oxo-7H-benzo [c] fluorenyl) oxy] ethyldimethylbenzylammonium chloride. 8. A process for the preparation of quaternary salts of the general formula I according to claim 1, characterized in that the substance is a Οφ o react with β compounds of the general formula and ₂ ch ₂ n; -CH 3 'CH, / 11 / III, XR (111) in which R is as defined above and X represents a chlorine, bromine or iodine atom in an inert medium, preferably ethanol, in the temperature range from 20 ° C to the boiling point of the reaction mixture. Severography, n. P., MOST