CS200094B1 - Derivatives of 3,9-dimethyl-5-hydroxy-7-oxo-7h-benzo/c/-fluorene - Google Patents

Description

The compounds of formula (I) have shown antineoplastic activity in animal studies with transplantable tumors and are potential chemotherapeutic agents for human cancer. For example, 3,9-dimethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene-6-carboxylic acid or 3,9-dimethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene , administered sc mice at a dose of 100 mg / kg, continuously for 10 days, significantly prolonged the lifespan of treated animals with S 180 and S 37 sarcomas compared to a control group of untreated animals. In addition, the compounds of the formula I are valuable intermediates for the synthesis of other pharmacologically active substances, in particular, for example, anti-viral and interferon-generating substances and anti-bacterial and disinfectant substances.

A compound of formula I in which R is a carboxyl group can be prepared, for example, from a compound of formula II

200 094

200 094

2.

CMj

(II) intramolecular cyclization, using anhydrous aluminum chloride, for example in an amount of 1 to 3 mol equivalents in an inert solvent such as 1,2-dichloroethane, at a temperature of from 20 ° C to the boiling point of the reaction mixture.

After cyclization, the reaction mixture is worked up in the usual manner for this type of reaction and the crude product is purified by crystallization from a suitable solvent or solvent mixture.

Other acid-reactive catalysts, such as sulfuric acid, polyphosphoric acid, tin tetrachloride, titanium tetrachloride or a mixture thereof with phosphorus pentoxide, may also be used for the intramolecular cyclization of the compounds of formula (II), optionally in a suitable medium and suitably selected reaction conditions. However, these methods are less suitable from an economic point of view.

The compound of formula 1 in which R is a hydrogen atom is prepared from a compound of formula

by treatment with sulfuric acid in acetic acid at temperatures from 100 ° C to the boiling point of the reaction mixture. After the reaction, the reaction mixture was poured into water. the precipitated organic fraction is filtered off with suction and purified by crystallization from a suitable solvent or solvent mixture.

The formation of a compound of formula I in which R is a hydrogen atom from a compound of formula III consists in the intramolecular cyclization of the transient monocarboxylic acid by treatment with sulfuric acid.

The starting materials of formulas II and III are prepared by a sequence of reactions from, -di-p-tolyl- <-dibromisocrotonic acid, which is known and readily prepared in high yield (M.Semonsky et al., Collection Czech Republic.Chem.Commun. 40, 2S69, 1975). Cyclization of γ,, -di-p-tolyl-βζ, -dibromisocrotonic acid chloride prepared by general methods for the preparation of carboxylic acid chlorides by treatment with 1 to 3 mol equivalents of Lewis acids, preferably zinc chloride or a mixture thereof with 10 to 50 wt. , in the melt, at temperatures of 20 to 100 ° C, for 1 to 5 hours, prepare! a compound of formula (IV) wherein R ^ is hydrogen,

200 094

ΗΛ

13k ftr (IV), which by reaction with known methylating agents gives a compound of formula IV in which Π denotes a methyl group. This material is nitrile by treating with excess cyanide in the tetramethylurea environment to give a compound of formula III which, when reacted with sulfuric acid in an acetic acid medium, provides a compound of formula II.

The compound of formula IV in which R @ 1 is methyl is prepared from a compound of formula IV in which it is hydrogen by treatment with 1 and 2 mol equivalents of a methylating agent, in an inert solvent or water, in the presence of acid scavengers at 20-100 ° C.

The compound of formula (III) is prepared by nitrilizing a compound of formula (IV) in which R1 is methyl, using 1 to 5 mol equivalents of cyanide in tetramethylurea at a temperature of from 100 ° C to the boiling point of the reaction mixture for 1 to 8 hours.

The compound of formula II can be prepared by reacting the compound of formula III with sulfuric acid in an acetic acid medium, preferably at a temperature of from 100 ° C to the boiling point of the reaction mixture, for 2-16 hours.

Further details of the preparation of the compounds of the formula I and of the compounds of the formulas II, III, IV are given in the following examples. In these examples, the melting points were determined on the Kofler block and are not corrected.

Example 1

7-Methyl-4-p-tolyl-2,3-dibromo-4-naphthol

To a suspension of 311 g (0.73 mol) of N, N-p-tolyl-, β-dibromoisocrotoric acid in

1000 ml of carbon tetrachloride was added dropwise to 96.5 g (0.81 mol) of thionyl chloride and 0.1 ml of dimethylformamide, and the reaction mixture was refluxed under exclusion of air humidity for 2.5 hours.

After the volatiles were distilled off in a water pump vacuum, 150 g (1.1 mol) of anhydrous zinc chloride and 22 g (15% by weight) of oxide were added to the residue, 4-di-p-tolyl-1,4-dibromisocrotonic acid chloride. and the mixture was heated to 80 ° C with stirring for 2 hours. After cooling to 20-25 ° C, the melt obtained is decomposed with water and the organics are taken up in chloroform. After concentration of the chloroform extract, the precipitated product is purified by crystallization from hexane. Melting point: 176-177 ° C.

200 094

Example 2

7-Methyl-4-p-tolyl-2,3-dibromo-1-methoxynaphthalene

In a solution of 22 g (0.56 mol) of sodium hydroxide in 280 ml of water, 162 g (0.4 mol) of 7-methyl-4-p-tolyl-2,3-dibromo-C-naphthol are dissolved, 66 g (0.52 mol) of dimethyl sulphate and the reaction mixture were heated to 80 ° C with stirring for 1 hour. After cooling, the reaction mixture was extracted with chloroform, the chloroform extract was dried and concentrated to crystallize. The crude product melts at 98-99 ° C after recrystallization from heptane.

Example 3

7-Methyl-4-p-tolyl-2,3-dicyano-1-methoxynaphthalene

To a suspension of copper (I) cyanide (100.2 g, 1.1 mol) in tetramethylurea (350 ml) was added 7-methyl-4-p-tolyl-2,3-dibromo-1-methoxynaphthalene (121 g, 0.29 mol) with stirring. The reaction mixture was heated at 150-150 ° C for 4 hours. After distilling off the tetramethylurea in a water pump vacuum, the residue is stirred with a mixture of 900 ml of benzene and 100 ml of methanol. After filtration of the inorganic fractions, the filtrate is concentrated to about 1/5 of the original volume and, after dilution with 200 ml of methanol, it is allowed to crystallize at 5 ° C. Crystallization of the crude product from benzene-methanol (1: 5) gave the product with a melting point of 179-181 ° C.

Example 4

7-Methyl-4-p-tolyl-1-methoxy-naphthalene-2,3-dicarboxylic acid anhydride

To a suspension of 20 g (0.064 mol) of 7-methyl-4-p-tolyl-2,3-doocyan-1-methoxynaphthalene in 600 ml of acetic acid and 300 ml of water, 300 ml of concentrated sulfuric acid is added dropwise with stirring, and the mixture is refluxed. 5 hours at 150-160 ° C. After cooling and diluting the reaction mixture with 3 liters of water, the precipitated organic substance is filtered off with suction and dried after washing with water. The crude product is hot-soaked with 750 ml of benzene and the benzene product is concentrated to crystallize. The crude product was recrystallized from benzene-methanol (1: 2); mp 159-162 ° C.

Example 5

3.9-Dimethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene

To a suspension of 20 g (0.064 mol) of 7-methyl-4-p-tolyl-2,3-dicyano-1-methoxynaphthalene in 670 ml of acetic acid and 200 ml of water is added dropwise with stirring 600 ml of concentrated sulfuric acid and the mixture is refluxed. hours. After cooling, the mixture is diluted with 3 liters of water, the precipitate formed is filtered off with suction and dried after washing with water. Crystallization of the crude product from chloroform-ethanol (1: 1) gave pure title compound G ^ 0 ^ ghj _of which sublimates from 260 ° C.

Example 6

3.9-Dimethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene-6-carboxylic acid

To a suspension of 6.65 g (20 mmol) of 7-methyl-4-p-tolyl-1-methoxynaphthalene-2,3-dicarboxylic acid anhydride in 200 ml of dichloroethane was added 5.6 g (42 g) at 20-25 ° C. mmol) of anhydrous anhydrous chloride and the reaction mixture is refluxed for 4 hours, then cooled and quenched by pouring into a mixture of 400 ml of water and 100 ml of concentrated hydrochloric acid. The precipitated crude product is filtered off with suction, washed with water and dried. Crystallization of the crude product from chloroform-ethanol (1: 1) gave the pure product, m.p. 243-246 ° C.

200 094

SUBJECT OF THE INVENTION

Claims (3)

SUBJECT OF THE INVENTION CLAIMS 1. 3,9-Dimethyl-5-hydroxy-7-oxo-TH * benro (c) fluorene derivatives of the general formula I, in which R represents a hydrogen atom or a carboxyl group. 2. 3,9-Dimethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene. 5. 3,9-Dimethyl-5-hydroxy-7-oxo-7-H-benzo (c) fluorene-6-carboxylic acid.