CS212670B1 - Derivatives of the 7-oxo-7h-benzo/c/fluorenes with antineoplastic effect - Google Patents

Abstract

The invention relates to novel antineoplastic agents 7-oxo-7H-benzo (e) - fluorene wherein R * is hydrogen or ethyl, R2 represents a hydrogen atom or a group -ch2ch2n (ch3) 2 and X represents a semicarbazide residue, thiosemicarbazide or aminoguanidine. Subject The invention also relates to salts of the compounds of the invention of Formula I with pharmaceutically acceptable salts organic or inorganic acids. Letters showed a distinct anti-tumor effect in animals with experimental implants tumors.

Description

The invention relates to 7-eye-7H-benzo (c) fluorene derivatives of the general formula 1

Wherein R represents a hydrogen atom or an ethyl group, R represents a hydrogen atom or a moiety of formula II

-ch ₂ ch ₂ n (ch ₃ ) ₂ (II) and X is a group of formula III,

N-HN-i-NHg (III)

Z 'in which Z represents an oxygen, sulfur or imino atom, as well as a process for their preparation.

i 2

For compounds of formula I in which R and X are as defined above and R is a group of formula II, the invention also relates to their salts with pharmaceutically acceptable organic or inorganic acids.

2

The compounds of formula (I), as defined above for R, R and X, showed an antitumor effect in animals with exp. tumors in mice with ascites tumors S 37 or Krebs 2, solid tumors S 180 (Crocker's sarcoma) or HK (adenocarcinoma of the mammary gland) or in rats with Yoshid's sarcoma.

In these experiments, the compounds were administered once daily at the doses indicated below. In mice with ascitic tumors 8x on days 1 to 5 and 7 to 9 post-transplantation, in mice with solid tumors 8x in a similar scheme, but starting on day 5 or 7 after transplantation. Tumor size was determined the day after the end of administration. Tumor size and survival time were compared to untreated animals (controls).

The inventors give examples of antitumor effect of some substances:

Thiosemicarbazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene: prolonged the survival of animals with Yoshid's tumor by 20 56 at a dose of 100 mg / kg s.c .;

Semicarbazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene: prolonged the survival of animals with Yoshid's tumor by 12% at 50 mg / kg bp reduced tumor size by 30% at 100 mg / kg sc

Guanylhydrazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene dihydrochloride: reduced HK tumor size by 21% at a dose of 100 mg / kg p.o. by 18% at a dose of 50 mg / kg s.c., reduced the tumor size of S 37 by 29%, respectively. o 21% at a dose of 50 mg / kg p.o., respectively.

c. while reducing the total cell count in the ascites by 16% and 16%, respectively.

%; reduced the tumor size of Kr 2 by 47%, respectively. 39%, at a dose of 100 mg / kg p.o. 50 mg / kg s.c., while decreasing the total amount of cells in ascites by 33 and 33%, respectively. 29% J Prolonged survival of animals with Yoshid's tumor by 23 in 50 mg / kg s. C.

Semicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene hydrochloride: reduced the tumor size of HK by 21%, respectively. o 17% at a dose of 100 mg / kg p.o., respectively. 50 mg / kg

s. c .; reduced the tumor size of Sa 37 by 40% at a dose of 50 mg / kg s.c., while reducing the total number of cells in the ascites by 46%; reduced the tumor size of Kr 2 by 27%, respectively. 47% at 100 mg / kg p.o., respectively. 50 mg / kg s.c., while reducing the total amount of cells in ascites by 28%, respectively. 50%; prolonged the survival time of animals with Yoshid's tumor by 65% at a dose of 50 mg / kg s. c.

Thiosemicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene: reduced Sa 37 tumor size by 25% at 50 mg / kg s.c.

2

The compounds of formula (I), as defined above for R, R and X, also showed a mild action against vaccinia virus and encephalomyocarditis.

2. Compounds of formula I in which R is ethyl, R is hydrogen and X is a group of formula III as defined above Z are prepared according to the invention from a compound of formula IV

by reaction with at least 1 mole equivalent, preferably with a 10 to 50% excess thereof, of the compounds of formula V

NH _{0 -} NH - C - NH ₀ (V)

I z

wherein, as defined above, in an inert medium, preferably ethanol, in the presence of acidic reactants, preferably acetic acid, in the range of from 40 ° C to the boiling point of the reaction mixture.

2

Compounds of the formula I in which R is a hydrogen atom, R is a group of formula II and X is a group of formula III, as defined above Z, are prepared according to the invention by condensation of a compound of formula VI

(VI) with compounds of formula V, as defined above, wherein compounds of formula V, as defined above, are used in an amount of at least 1 mol equivalents, preferably 2 to 10 mol equivalents, and the condensation is carried out in an inert solvent, preferably in ethanol, in the presence of acidic reagents, preferably in the presence of acetic acid, or in a neutral environment, in the temperature range from 40 ° C to the boiling point of the reaction mixture.

Compounds of formula IV and VI used as starting compounds for the synthesis of compounds of formula I 2

I, having the meanings given above for R, R and X, the substances are known and readily transportable according to our cf. No. 202 213 and 212 669.

Ř

2.2670

The reaction mixtures after the condensation have been worked up according to the obligatory methods for said types of reactions; for example, after cooling the reaction mixture, the precipitated compounds are aspirated and purified by crystallization, or the reaction mixtures are concentrated to dryness and the crude product is purified by crystallization or silica gel column chromatography. Substances containing a basic group molecule can be converted into addition salts with organic or inorganic acids , preferably in an environment of lower alcohols, ethanol or methanol. Suitable pharmaceutically acceptable acids are, for example, tartaric, butyric, napsylic, fumaric, citric, malic, hydrochloric, sulfuric, methane- and ethanesulfonic acids.

2

More detailed information on the preparation of the compounds of formula I, as defined above for R, R and X, will be apparent from the following non-limiting examples.

He did

Thiosemicarbazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene

To a solution of 3.0 g (10 mmol) of 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) ^and Fluo ene in 100 ml of ethanol was added 2 ml of conc. acetic acid and 10 g (11 mmol) of thiosemicarbazide and the reaction mixture is refluxed for 12 hours, cooled, diluted with 50 ml of water and the precipitate formed is filtered off with suction, washed with water and recrystallized from ethanol. Melting point: 228-230 ° C.

Using the analogous procedure, starting from 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene, the following were prepared:

Semicarbazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene, mp 248-252 ° C (benzene-ethanol);

Guanylhydrazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene, m.p. 180-183 ° C (ethanol-water).

Example 2

Thiosemicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene

To a solution of 317 mg (1 mmol) of 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (o) fluorene in 10 ml of ethanol and 0.5 ml of acetic acid is added 0.5 g of thiosemicarbazide (5 ml). (5 mmol) and the reaction mixture was refluxed for 10 hours and evaporated to dryness after completion of the reaction. The residue is taken up in 50 ml of water, basified with conc. aqueous ammonia solution and the precipitate is taken up in chloroform. The chloroform extract was dried and the crude product was purified by silica column chromatography using chloroform as eluent. Pooling of the single fractions and crystallization from chloroform-ethanol gave a melting point of 112-113 ° C.

Example 3Semi-carbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene

To a solution of semicarbazide acetate in 20 ml of ethanol prepared from 2.0 g of sodium acetate and 2.0 g of isicicarbazide hydrochloride after filtering off the undissolved fractions was added 317 mg (1 mmol) of 5- [2- (dimethylamino) ethoxy]. -7-oxo-7H-benzo (c) fluorene and the reaction mixture was refluxed for 1 hour. The precipitate formed on cooling is filtered off with suction and recrystallized from aqueous ethanol. Mp 245-246 ° C.

Example 4

Semicarbazone hydrochloride 5- [2- (dimethylemino) ethoxy] -7-oxo-7H-benzo (c) fluorene

To a solution of 374 mg (1 mmol) of semicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene prepared as described in Example 3 in 10 ml of ethanol is added 1 ml of ethanolic hydrogen chloride solution. (saturated solution), and concentrated to crystallize to give a melting point of 280-282 ° C.

Example 5

Guanylhydrazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene dihydrochloride

To a solution of 3.53 g (10 mmol) of 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene in 250 mL of ethanol was added 2.1 g (28.7 mmol) of aminoguanidine (released from hydrogen carbonate with an equivalent amount of sodium hydroxide) and the reaction mixture is refluxed for 10 hours and then evaporated to dryness. The crude product was purified by passage through a silica column using chloroform-20% ethanol as eluent, the fractions were concentrated and neutralized with ethanolic hydrogen chloride solution. Crystallization from ethanol gave a melting point of 268-270 ° C.

Claims (11)

CLAIMS 1. Antineoplastic active derivatives of 7-oxo-7H-benzo (c) fluorene of the general formula I In which B represents a hydrogen atom or an ethyl group, R represents a hydrogen atom or a group of the formula XI -ch ₂ ch ₂ n (ch ₃ ) ₂ (II) and X denotes the group of the general formula III N-HN-C-NH, (III) 1 Z in which Z represents an oxygen atom, a sulfur atom or an imino group. 1 2 2. Salts of compounds of formula I wherein R and X are as defined above and R is a group of formula II with pharmaceutically acceptable organic or inorganic acids. 3. Semicarbazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene. 4. Thiosemicarbazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene. 5. Guanylhydrazone 3,9-diethyl-5-hydroxy-7-oxo-7H-benzo (c) fluorene. 6. Semicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (e) fluorene. Semicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene hydrochloride. 8. Thiosemicarbazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene. 9. Ouanylhydrazone 5- [2- (dimethylamino) ethoxy] -7-oxo-7H-benzo (c) fluorene dihydrochloride A process for the preparation of 7-oxo-7H-benzo (c) fluorene antineoplastically active derivatives of formula (1), wherein R ¹ is ethyl, R ² is hydrogen and X is a group of formula (III) as defined above; by condensing a compound of formula IV with at least 1 mole equivalent, preferably with a 10 to 50% excess thereof, of a compound of formula V nh ₂ -nh-c-nh ₂ (V) wherein Z is as defined above, in an inert medium, preferably in ethanol, in the presence of acetic acid, in the temperature range from 40 ° C to the boiling point of the reaction mixture. 11. A process for the preparation of a compound of formula (I) wherein ^L @ ¹ is hydrogen, R @ ² is a group of formula (II) and X is a group of formula (III), as defined above, characterized in that O, ch ₃ 'and ₃ (VI) e compounds of formula V, as defined above Z, wherein ee compounds of formula V, as defined above, Z are used in an amount of at least 1 mol equivalents, preferably 2 to 10 mol equivalents, and condensation is carried out in an inert solvent, preferably ethanol, in the presence of acidic reagents, preferably in the presence of acetic acid, or in a neutral environment, in the temperature range of 40 ° C to the boiling point of the reaction mixture. , is converted by neutralization with a pharmaceutically acceptable inorganic or organic acid into the corresponding editorial salt.