CS262598B1 - S-Substituted 7-oxo-7H-benzo (c) fluorene derivatives and processes for their preparation - Google Patents

Abstract

The subject of the solution are derivatives of 7-oxo-7H-benzo(c)fluorene of the general formula I in which R denotes a piperidine, N-methyl-piperazine and morpholine residue, which can be prepared by the reaction of 5-hydroxy-7-oxo-7H-benzo-(c)fluorene with heterocyclic amines in a pyridine environment using paraformaldehyde. These substances showed an antitumor effect in biological evaluation.

Description

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

wherein R is piperidine, N-methylpiperazine and morpholine.

The compounds of formula I as defined above R are benzo (c) fluorene derivatives which are known to exhibit different biological activities potentially useful in human and veterinary medicine, depending on the type of substituent and its position on the aromatic backbone (see e.g. AO 212 669 and 217 731 and the publications Křepelka J., Roubík J., Holubek J., Vancurová II, Coll. Czech, Chem. Commun. .:

Coll. Chem. Commun. 4, 1867 (1982).

The compounds of formula (I) of the above-mentioned meaning of R have shown an antitumor effect in animals with experimental tumors in a biological evaluation. For 5-hydroxy-6- (1-morpholinylmethyl) -7-oxo-7H-benzo (c) fluorene in an in vitro experiment on Yoshid's tumor cells by simultaneous incorporation of 5-iodo-2-deoxy / 6H (uridine and (U-C) amino acid mixtures outweigh inhibition of DNA synthesis (IC 50 g 9.10 ^- mol mol.l ^{- 1} ) over inhibition of proteosynthesis (IC 50 g 2.4.10 ⁵ mol.l 1). 5-hydroxy-6- (1-methylpiperazinylmethyl) -7-oxo-7H-benzo (c) fluorene in animals with experimental tumors reduces tumor weight of B16 at 150 mg / kg by 3% and leukemia L1210 at 2x75 mg / kg prolongs the survival of the animals by 8% compared to the untreated control.

Compounds of formula I wherein R is piperidine, N-methylpiperazine and morpholine are prepared according to the invention from a compound of formula II

by reaction with at least 1 mole equivalent of compounds of formula III

R = (III) wherein R is a piperidine, N-methylpiperazine and morpholine moiety in pyridine and paraformaldehyde at 60 ° C. The compound of formula II is a known substance and is described (see Vancurova I., Simonova M., Benes J., Křepelka J .: Cesk. Fram. 31, 308 (1982)).

More detailed information on the preparation of the compounds of formula (I) will be apparent from the following non-limiting example.

Example

5-hydroxy-6- (1-piperidinylmethyl) -7-oxo-7H-benzo (c) fluorene mg (0.000 2 mol) 5-hydroxy-7-oxo-7H-benzo (c) fluorene is dissolved in 1 ml pyridine 0.1 ml of 35% paraformaldehyde and 0.2 ml of piperidine are added and stirred for 3 hours at 60 ° C. The precipitate formed is filtered off with suction and crystallization of the crude product from ethanol gives o; m.p. Mp 144-145 ° C.

The following were prepared analogously:

5-hydroxy-6- (1-methylpiperazinylmethyl) -7-oxo-7H-benzo (c) fluorene, m.p. 198 DEG-200 DEG C. (chloroform;

5-hydroxy-6- (1-morpholinylmethyl) -7-oxo-7H-benzo (c) fluorene, m.p. 121-125 ° C (chloroform)

Claims (5)

I will invent the object 6-substituted 7-oxo-7H-benzo (c) fluorene derivatives of formula X OH O CH ₂ R wherein R is piperidino, N-methylpiperazino and morpholino. 2. 5-Hydroxy-6- (1-piperidinylmethyl) -7-oxo-7H-benzo (c) fluorene. 3. 5-Hydroxy-6- (1-methylpiperazinylmethyl) -7-oxo-7H-benzo (c) fluorene. 4. 5-Hydroxy-6- (1-morpholinylmethyl) -7-oxo-7H-benzo (c) fluorene. 5. A process according to claim 1, wherein R is as defined above, characterized in that the compound of formula II OH O (II) is reacted with compounds of formula III (III) wherein R is as defined above in pyridine and paraformaldehyde at 60 ° C.