CS225002B1 - The derivates of 9-phenyl-1h-benzo /f/isoindole-1,3-dione and their production - Google Patents

Abstract

The present invention relates to novel derivatives of 9-phenyl- -1H-benzo (f) isoindole-1,3-dione substituted in position 2 and 4, which shows the general wherein R is 2-hydroxyethyl- or 2- 2 -chloroethyl and R is hydroxy or a 2-hydroxyethylamine or 2-chloroethylamine residue. These substances have an antitumor effect in animals with experimental tumors. Way their production consists in the reaction of anhydrides of 4-phenyl-1-alkoxynaphthalene-2,3-dicarboxylic acid with ethanolamine at elevated temperatures, leading to subst. benzo (f) isoindole 1,3-dione. The 2-hydroxyethyl compounds formed by boiling with thionyl chloride 2-chloroethyl compounds.

Description

The present invention relates to novel 9-phenyl-1H-benzo (f) isoindole-1,3-dione derivatives substituted at the 2- and 4-positions, which illustrates the general

wherein R is 2-hydroxyethyl- or 22

-chloroethyl and R is hydroxy or a residue of 2-hydroxyethylamine or 2-chloroethylamine.

These substances have an antitumor effect in animals with experimental tumors. A process for their preparation consists in reacting 4-phenyl-1-alkoxynaphthalene-2,3-dicarboxylic acid anhydrides with ethanolamine at elevated temperature to form the subst. benzo (f) isoindole-1,3-dione. The resulting 2-hydroxyethyl compounds are converted to the corresponding 2-chloroethyl compounds by boiling with thionyl chloride.

221) 002

The present invention relates to 9-phenyl-1H-benzo (f) isoindole-1,3-dione derivatives of formula (I)

(II) also relates to a method of manufacture

2 in which R is 2-hydroxyethyl or 2-chlorathylskuplnu and R represents hydroxyl or a group of the formula II CH ₂ NHCH ₂ R ³ wherein R ³ is chlorine or hydroxy. The invention of said substances.

2

The compounds of formula (I), as defined above for R and R, have shown an antitumor effect in biological evaluation in experimental animals and are therefore potential cancer chemotherapeutics for both human and veterinary practice. These substances also showed therapeutic effect in dishwashers with ascitic form of Sa 37 tumor and solid tumor of HK (mammary gland adanocarcinoma), and in rats with Yoshida tumor. In these experiments, the compounds were administered once daily at 100 and 200 mg / kg p.o. or a. C., In mice with ascitic or solid tumors 8 times on days 1 to 5 and 7 to 9 after tumor transplantation. In the case of Xoshid tumor, the compounds were administered to rats 5x, 1 to 5 days after transplantation. Tumor size was determined the day after treatment and compared to untreated controls. The test substances showed an inhibitory effect on the growth of ae tumors ranging from 15 to 40% and a survival of Xoshid's tumor by about 10 to 40%. 2- (2-hydroxyethyl) -4- (2-hydroxyethylamino) -9-phenylbenzo (f) isoindole-1,3-dione, which reduced the tumor size of Sa 37 at a dose of 200 mg / kg administered after 33%, with a simultaneous 15½ survival extension. It further prolonged the survival of animals with Xoshid tumor by 38% and, by a. C. Administration of the same dose, reduced the tumor size of HK by 26% while not affecting survival. Similarly, 2- (2-chloroethyl) -4- (2-chloroethylamino) -9-phenylbenzo (f) isoindole-1,3-dione at a dose of 100 mg / kg sc reduced the tumor size of Sa 37 by 17%, dose by 20% and prolonged the survival of animals with tumor X by 10 µl.

2

The compounds of formula I wherein R is 2-hydroxyethyl, and R represents hydroxyl or a group of formula II in which R ^J of the invention are prepared from compounds of formula III

according to (III) in which the fu is methyl or ethyl, by reaction with ethynolamine in the temperature range from 80 ° C to the boiling point of the reaction mixture, the ethanolamine being used as the reaction medium for 2 to 8 hours.

After the reaction, the reaction mixture is worked up in the usual manner, for example, after pouring into water and acidifying, the precipitate formed is filtered off with suction, washed with water to remove soluble constituents and dried.

The compounds of the formula I in which R @ ¹ denotes a 2-chloroethyl group and R @ ² denotes a hydroxy group or a group of the formula II in which R @ ³ denotes a chlorine atom according to the invention

2 are prepared by reacting compounds of formula I wherein R is 2-hydroxyethyl and R is

228002 denotes a hydroxy group or a group of formula II wherein R 1 denotes a hydroxy group by reaction with thionyl chloride, the thionyl chloride being used as the reaction mixture for up to 8 hours.

After the reaction, the reaction mixture is worked up in the usual manner, for example, after distilling off the volatiles in a water pump vacuum, the residue is purified by crystallization.

The substances of the general formula (III) used as starting materials are substances known and readily obtainable, e.g. No. 204 211.

For further details on the preparation of the compounds of formula (I), the above-mentioned meaning of phi 'and phi

R will be apparent from the following non-limiting examples.

He did

2- (2-Hydroxyethyl) -4- (2-hydroxyethylamino) -9-phenyl-1H-benzo (f) isoindole-1,3-dione and 2- (2-hydroxyethyl) -4-hydroxy-9-phenyl- 1H-benzo (f) isoindole-1,3-dione

A solution of 20.0 g (0.063 mol) of 4-phenyl-1-methoxynaphthalene-2,3-dicarboxylic acid anhydride in 10¾ ml of ethanolamine is refluxed for 8 hours and, after cooling, poured into 1700 ml of water and acidified with dilute hydrochloric acid (1). The precipitate formed is filtered off with suction, washed with water, dried and dissolved in approximately 300 ml of chloroform. Extraction with 5% sodium hydroxide and acidification of the aqueous portion with dilute hydrochloric acid (1: 1) gave a precipitate which, after washing with water, drying and recrystallization from chloroform-methanol (5: 1) afforded 2- (2-hydroxyethyl) -4- 210 DEG-2.2 DEG C. hydroxy-9-phenyl-1H-benzo (f) isoindole-1,3-dione.

The chloroform fraction remaining after the extraction with lye is dried over anhydrous sodium sulphate and concentrated to crystallize. 2- (hydroxyethyl) -4- (2-hydroxyethylamino) -9-phenyl-1H-benzo (f) isoindole-1,3-dione is obtained, m.p. 182-114 ° C.

The same products were prepared using 4-phenyl-1-ethoxy-naphthalene-2,3-dicarboxylic anhydride as starting material.

Example 2

2- (2-Chloroethyl) -4- (2-chloroethylamino) -9-phenyl-1H-benzo [f] soindole-1,3-dione

A suspension of 3.76 g (0.01 mol) of 2- (2-hydroxyethyl) -4- (2-hydroxyethylamino) -9-phenyl-1H-benzo (f) isoindole-1,3-dione in 10 ml of thiochloride is refluxed 1 hour. After cooling and evaporation of the volatiles in a water-jet vacuum, the residue is recrystallized from benzene to give a melting point of 157-158 ° C.

Example 3

2- (2-Chloroethyl) -4-hydroxy-9-phenyl-1H-benzo (f) isoindole-1,3-dione

A suspension of 3.3 g (0.01 mol) of 2- (2-hydroxyethyl) -4-hydroxy-9-benzo (f) isoindole-1,3-dione in 1.0 ml of thionyl chloride is refluxed with stirring for 6 hours and it was then worked up in the same manner as in Example 2. Crystallization from benzene gave a melting point of 198-199 ° C.

Claims (2)

Wherein R is 2-hydroxyethyl or 2-chloroethyl and R is hydroxy or a group of formula II NHCl 2 CH ³ R ^{3 (II)} > wherein R R represents a chlorine atom or a hydroxy group. 2- (2-Hydroxyethyl) -4- (2-hydroxyethylamino) -9-phenyl-1 H -benzo (f) isoindole-1,3-dione. λ 2- (2-Hydroxyethyl) -4-hydroxy-9-phenyl-1H-benzo (f) isoindole-1,3-dione. 4. 2- (2-Chloroethyl) -4- (2-chloroethylamino) -9-phenyl-1H-benzo [f] soindole-1,3-dione. 5. 2- (2-Chloroethyl) -4-hydroxy-9-phenyl-1H-benzo [b] isoindole-1,3-dione. 6, process for preparing compounds of formula I in which R ¹ represents 2-hydroxyethyl and R2 represents hydroxyl or a group of formula II in which R represents OH, characterized by reacting with a compound of general formula III CcHc OR ⁴ \ O x wherein R ⁴ is methyl or ethyl, with ethanolamine ranging from 80 ° C to the boiling point of the reaction mixture, wherein the ethanolamine is used as the reaction medium for 2 to 8 hours. 7. A process for preparing compounds of formula I wherein R ¹ denotes a 2-chloroethyl 1. 9-Phenyl-1H-benzo (fisoindole-1,3-dione derivatives of the general formula I) And R is hydroxy or a moiety of formula (II) wherein R is chlorine by reacting compounds of formula (I) wherein R is 2-hydroxyethyl and R is hydroxy (prepared according to point 6) with thionyl chloride, the thionyl chloride being used as the reaction medium, at the boiling point of the reaction mixture, for 1 to 8 hours.