CS239413B1 - N-oxides of 5- (dialkylamino) alkoxy-7-oxo-7H-benzo / c / fluorene derivatives and a process for their preparation - Google Patents

Abstract

Antineoplastically active N-oxides in general and a method for their production, consisting in the oxidation of tertiary amino groups in basic ethers derived from 5-hydroxy-7-oxo-7H-benzo[c]fluorene, by the action of peracetic acid or 3-chloroperbenzoic acid in an inert medium of chloroform.

Description

The invention relates to N-oxides of 5-(dialkylamino)alkoxy-7-oxo-7H-benzo[.c]fluorene of general formula I

2 in which R represents a hydrogen atom, a methyl or ethyl group, R represents a methyl or ethyl group and Z represents a carbon chain with two or three methylene groups or a neopentyl group of formula II,

-ch ₂ -c/ch ₃ / ₂ -ch ₂ - (II), as well as the method of production of the said substances.

The compounds of general formula I, with the above-mentioned meanings of R, R and Z, are derivatives of basic ethers derived from 5-hydroxy-7-oxo-7H-benzo/c/fluorene, which show significant antitumor and antileukemic effects in animals with experimental transplantable tumors. (More details are given in the Czechoslovak author's certificate No. 212 669). From the mentioned group of compounds, 5-/2-(N,N-dimethyl)aminoethoxy/-7-oxo-benzo/c/fluorene hydrochloride, working name benflurone (substance VÚFB-,3 468), was selected for preclinical development and is now in the phase of clinical testing. From the structure of benflurone and its analogues, a number of biotransformation transformations can be assumed, of which N-oxidation is among the most significant. The presence of N-oxide in a molecule generally changes the character of the original substance in terms of lipophilic properties and introduces a new effector function into the molecule, and also changes the probable mechanism of action of the original substance. Moreover, N-oxides are the first products of biooxidative transformation of the original substance in vitro by enzymes of the microsomal fraction of the liver of experimental animals (bulletin czs. spol. biochemika při ČSAV vol. 11, 1983, no. 3, abst. 5-37, Nobills et al.).

2

The compounds of general formula I, with the above-mentioned meanings of R 1 , R 2 and Z, have useful antitumor activity and can be used alone or in combination with other antineoplastics as an active ingredient of pharmaceutical preparations for the treatment of suitable biological objects bearing tumors, especially of mammalian origin.

By treatment is meant the inhibition of characteristic symptoms of the disease of a suitable biological object bearing a tumor, for example, tumor growth, shortening of the lifespan of the biological object, increase in the number or growth of tumor cells, and the like.

Tumor growth can be observed clinically or in experiments in vivo. i.e. on experimental animals, or in vitro. for example on tissue cultures prepared from tumors. Tumor growth can be determined for example by weighing the tumor mass or, more efficiently, by measuring radioactivity after incorporation of certain substances of natural origin, such as amino acids, adenine, thymidine, etc., labeled with radioactive atoms, such as ¹ ^C, ³ H, etc.

For example, 5-(2-(N,N-dimethylamino)ethoxy)-7-oxo-7H-benzo[c]fluorene N-oxide was administered in the form of an aqueous solution orally to 120 mice with Ehrlich tumor and HK tumor and to 60 mice with DBA? 8 leukemia ⁱⁿ the esic form. The tumor weight and survival time of the animals were monitored against the control.

The results are summarized in the following table I:

Tumor Dose (mg/kg/day)

Tumor weight (in % of control)

Relative survival (in % of control)

STB 2x 300 p.e. + 2x 150 p.o. Shi 4· 127 HE 8x >50 p.o. 12 + 111 and 8x 50 s.c. 82 ♦ 108 8x 25 s.c. 12 + 99 ^L 1210 4x 100 p.e. - 84 4x 50 p.o. - 104 4x 50 s.c. - isa 4x 25 s.c. - 98 2x 150 p.e. - 247 2x 75 p.e. • 116 ♦underlined values are statistically significantly different from the inspection (p 0.05)

♦♦surviving animals euthanized + ++ +

+ +

The results show that the substance statistically significantly (p 0.05) reduces the average weight of tumors and statistically significantly prolongs the life span of animals with experimental tumors.

In an in vitro experiment with Yeshidev tumor cells, the initial rate of incorporation of 5-iodo-2*-deexy 6-^H uridine and a mixture of L- U-' ⁴ C amino acids was monitored and its influence by different concentrations of the tested substances was determined. From the dependence of the initial rate on the concentration, the concentration reducing the rate of incorporation to half the rate of unaffected cells (IC^q) was determined.

The results are summarized in Table II:

Compound Rel, mol. IC^q

No. VÚřB weight (mmel.1 ^- ')

5-I-de-U amino acid blend

14 283 333.37 66 100 15 741 375.4 24 41 15 742 389.5 15 39 15 753 391.5 39 100

283 - 5-[2-(N,N-dimethylamine)ethoxy]-7-oxe-7H-benzo[c]fluerett N-oxide

5 741 - 5-(N,N-dimethylamine)-2,2-dimethylprepoxy-7-exo-7H-benzene/c/fluorene N-oxide

742 - N-exide 3,9-dimethyl-5-(2-(N,N-diethylamine)ethoxy-7-oxe-7H-benzene/c/fluerene 15 752 - N-exid 3,9-diethyl-5-(2-(N,N-dimethylamine)ethoxy-7-oxe-7H-benzene/c/fluerene 15 753 - N-exid of 1-diethylimine-3-(5-(7-exe-7H-benzene/c/fluerenyloxy)-2-propanel).

An analogous experiment with substance 15 752, rel. mel. wt. 389.5, in combination with an equimolar concentration of benfluor, i.e. 5-/2-(N,N-dimethylamine)ethexy-7-exe-7H-benze/c/fluerene, led to similar results, which indicates an increase in the effectiveness of the combination. The previous data clearly demonstrate that the described compounds are effective inhibitors of DNA biosynthase and protein synthesis, which explains their antitumor effect in vivo.

2

The compounds of the general formula I, in which R , R and Z have the above-mentioned meanings, can be prepared by conventional procedures for the preparation of N-oxides from tertiary amino compounds by the action of organic peracids in an inert environment. The choice of oxidation conditions depends on the nature and properties of the starting tertiary amino compound. According to the invention, the N-oxides of the general formula I, in which R ¹ ,

R ^z and Z have the above meanings, I prepare from substances of general formula III,

OZN' ^X R ² (III) has the meaning as in general formula I by the action of organic 1 to 2 molar equivalents, in an inert environment, preferably Bd 0 to 40 °C.

R ¹ in which R ¹ , R ² and Z have the same peracids, used in Amounts in chloroform, in the temperature range <

Of the organic peracids, it is possible to use all commonly available aliphatic peracids or aromatic peracids, with peracetic acid and, from an economic point of view, 3-chloroperbenzoic acid being preferred.

Aromatic or chlorinated hydrocarbons, preferably chloroform, can be used as an inert medium for reactions with peralkylenes.

The reaction mixture after oxidation is carried out is treated by the usual methods for this type of reaction, for example, the reaction mixture is washed with sodium bicarbonate solution, water and the crude product obtained after concentration is purified by crystallization. Benzo/c/fluorene 1 2 derivatives of the general formula III, with the above-mentioned meaning of R , R and Z, are substances known and easily prepared according to Křepelka J. et al.: Collection Czech. Chem. Commun. 47, 1 856 (1982).

More detailed information on the preparation of the substances will be found in the following examples, which, however, do not limit the scope of the invention in any way.

Example

5-(2-(N,N-dimethylamino)ethoxy/3-7-oxo-7H-benzo/c/fluorene N-oxide

To a solution of 790 mg (2.5 mmol) of 5-[2-(N,N-dimethylemino)ethoxy]-7-oxo-78-benzo[c]fluorene in 7.5 ml of chloroform at room temperature was added portionwise 772 mg (4.5 mmol) of 3-chloroperbenzoic acid and the reaction mixture was stirred for 8 h. After completion of the reaction, the mixture was evaporated to dryness. Crystallization from chloroform gave the title compound, m.p. 92-94 °C.

The following are prepared in the same way:

5-[3-(N,N-dimethylamino)-2,2-dimethylpropoxy]-7-oxo-7H-benzo[e]fluorene N-oxide with m.p.

109 to 111 °C,

5-[3-(N,N-dimethylamino)propoxy]-7-oxo-7H-benzo[c]fluorene N-oxide with m.p. 121 to 123 °C,

3,9-Dimethyl-5-(2-(N,N-diethylamino)ethoxy)-7-oxo-7H-benzo[c]fluoroene N-oxide, m.p. 118 to 120 °C,

3,9-diethyl-5-[2-(N,N-dimethylamino)ethoxy]-7-hexa-7H-benzo[c]fluorene N-oxide with a melting point of 160 to 162 °C and

1-Diethylamino-3-(5-(7-oxo-7H-benzo[c]fluorenyloxy)/-2-propanol N-oxide with m.p. 132 to 134 °C.

Example 2

To a solution of 634 mg (2 mmol) of 5-(2-(N,N-dimethylamino)ethoxy)-7-oxo-7H-benzo[c]fluorene in 20 ml of acetic acid was added 380 mg (5 mmol) of peracetic acid and stirred at room temperature for 48 h. The reaction mixture was neutralized with 10% aqueous potassium hydroxide, extracted with chloroform, the extracts were dried over sodium sulfate and evaporated. Crystallization from chloroform gave 5-(2-(N,N-dimethylamino)ethoxy)-7-oxo-7H-benzo[c]fluorene N-oxide with a m.p.

up to 93°C.

Claims (10)

SUBJECT OF THE INVENTION 1- N -oxide of 5- (dialkylamino) alkoxy-7-oxo-7H-benzo [c] fluorene derivatives of the general formula I wherein R ¹ represents a hydrogen atom, a methyl or ethyl group and Z represents a carbon chain with or a neopentyl group of formula II O ethyl, R is methyl or two or three methylene groups -ch ₂ -c (ch ₃ ) ₂ -ch ₂ (II). 2. N-oxide 3. N-oxide 4. N-oxide 5. N-oxide 6. N-oxide 7. N-oxide 8. Method of general substance 5- [2- (Ν, Ν-dimethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene. 5- [3- (N, N-dimethylamino) -2,2-dimethylpropoxy] -7-oxo-7H-benzo [c] fluorene. 5- [3- (N, N-dimethylamino) propoxy] -7-oxo-7H-benzo [c] fluorene. 3.9-Dimethyl-5- [2- (N, N-diethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene. 3.9- diethyl-5- [2- (N, N-dimethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene. 1-dimethylamino-3- [5- (7-oxo-7H-benzo [d] fluorenyloxy)] - 2-propanol. The preparation of the compounds of the formula I according to claim 1, characterized in that for the formulas III 0, 2 (XII), The peracids used in an amount of 1 to 2 meqlvalents in an inert medium, preferably chloroform, in the temperature range from 0 to 40 ° C. 9. Process according to claim 8, characterized in that 3-chloroperbenzoic acid is used for the oxidation. 10. A process according to claim 8, wherein peracetic acid is used for the oxidation.