CS217731B1 - Biologically effective basic ester-ethers 7-oxo-7h-benzo/c/-fluorene,the salts thereof and method of preparation of the same - Google Patents

Abstract

Biologically active ester-ethers 7-oxo-7H- -benzo (c) fluorene and its 3,9-dimethyl-, respectively. 3,9-diethylanaloga of formula I in which R 1 is hydrogen, methyl or ethyl, R 2 is a basic residue. Substances are prepared by alkylation of 5-hydroxy-6- -carboxy-7-oxo-7H-benzo (c) fluorene, respectively. its analogues. The compounds of formula (I), respectively. their salts exhibit antiviral, interferonogenic and antineoplastic effect.

Description

The present invention relates to biologically active basic ethers of 7-oxo-7H-benzo (c) fluorene of formula I

in which

R ¹ is hydrogen, methyl or ethyl,

R ² denotes a group of the general formula II R ³

OF

- (CH 2) _X N II,

R5 in which

R ³ is methyl or ethyl; and x is an integer of 2 or 3, or a moiety of formula III

CH3

From —CH2 — C (CH3) 2 —CH2N III, \

CH3 and their salts with pharmaceutically acceptable inorganic or organic acids. The invention also relates to the preparation of the compounds of formula I.

Compounds of formula I for the above mentioned meaning of R ¹ and R ² showed biological evaluation antiviral and antineoplastic effect.

The antiviral activity of the compounds was evaluated against encephalomyocarditis virus (EMC) (Bratislava strain) and vaccinia virus (vaccinium variolae, SEVAC, OSOL Prague) in female SPF mice. The substances were applied in the form of aqueous solutions or in suspension with Tween 80 p. O., By gavage or s. C. To the skin fold on the back. They were administered once at 24 hours prior to infection, at 4 times, 28, 22 and 2 hours prior to infection, at 4 times, 28, 22, and 2 hours before infection, and 2 hours after infection. [Adrews E. R. et al., J. Med. Chem. 17, 882 (1974)].

The EMC virus was administered sc and the LD 50 of the virus was determined by a conventional method. Vaccinia virus was administered intravenously at 1.25 x ^{10 5} and 2.5 x ^{10 4} infectious units, which produced necrotic lesions on the tail of the animal on days 6 and 8. Evaluation of the effect of the compounds was performed on the survival percentage of treated and infected mice for the EMC virus and the percent inhibition of necrotic forests on the tail of the mouse, both relative to untreated controls, for the vaccinia virus.

All studied substances showed antiviral activity against EMC virus as well as vaccinia virus. The intensity of action depended on the route of administration and the dose. The following are some of the effects of some substances: 5- [2- (dimethylamino) ethoxy] -6- [2- (dimethylamino) ethoxycarbonyl] -7-OXO-7H-) benzo [c] fluorene dihydrochloride at 50 mg / kg 50% and at a dose of 250 mg / kg 100% survival of infected animals with EMC virus. When administered at 50 mg / kg at 4 time intervals, 62% of the animals with EMC virus survived.

At a dose of 25 mg / kg p.o. inhibited 50% of necrotic lies, and with s. C. Administration of 4X25 mg / kg inhibited 70% of lesions in animals with vaccinia virus. LD 50 s.c. - 1140 mg / kg, LD 50 s.c. = 230 mg (SPF mice).

5- [2- (diethylamino-ethoxy) -6- [2-diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride at a dose of 100 mg / kg after survival of 60% of animals and at a dose of 4X50 mg / kg sc caused survival of 50% of animals with EMC virus. At a dose of 50 mg / kg p.o. inhibited 50%, and with s. C. Application of 4X25 mg / kg inhibited 70% of lesions in animals with vaccinia virus. LD 50 i.v. = 15.5 mg / kg (male mice), 14.0 mg / kg (female), p.o. - 400 mg / kg (female).

3.9-dimethyl-5- [2- (diethylamino) ethoxy] -6- [2- (diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride inhibited 50% of the tail lesions in a dose of 4X50 mg / kg of animals with vaccinia virus.

3.9- diethyl-5- [2- (diethylamino) ethoxy] -6- [2- (diethylamino) ethoxycarbonyl) -7-. -oxo-7H-benzo [c] fluorene dihydrochloride at a dose of 100 mg / kg p.o. caused a survival rate of 60% and a dose of 4 X 50 mg / kg s. c. caused a survival of 28% of animals with EMC virus. Upon administration of 100 mg / kg, he inhibited 50% of lesions and, at a dose of 4X25 mg / kg, inhibited 59% of lesions of vaccinia virus animals. LD 50 - 80 mg / kg i.v. (male mice), 65 mg / kg i.v. (female mice), 900 mg / kg p.o. (female mice).

5- (3- (dimethylamino) -2,2-dimethylpropoxy) -6- (3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride inhibited tail lesions from 60% at 4X50 mg / kg sc

5- (3- (dimethylamino) -2,2-dimethylpropoxy) -6- [3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxobenzo-7H-benzo (c) fluorene inhibited vaccine lesions at 4X50 mg / kg sc of 90%.

Some of the tested substances showed interferonogenic activity. The compounds were administered to animals at a concentration of 250 mg / kg p.o. and the mice were bled after 24 hours and the serum in L-929 cell culture was cultured at 37 ° C. After serum removal and washing, tissue was infected with EMC virus and the cytopathic (CPE) effect of the virus was read 24 and 48 hours after infection. The presence of interferon was determined by inhibiting the cytopathic effect of the virus, with an interferon titer equaling the dilution that suppressed 50% of the EMC CPE. Of the study group, 5- [2- (dimethylamino) ethoxy] -6- [dimethylamino) ethoxycarbonyl] -7-oxo- [c] fluorene dihydrochloride proved to be the most active substance.

Some selected agents were also evaluated for antitumor effect in animals with experimental transplatable tumors, in mice with ascitic tumors S 37 and Kr 2, solid tumor HK, or in rats with Yoshid sarcoma.

3.9-Diethyl-5- [2- (diethylamino) ethoxy] -6- (2- (diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride at a dose of 100 mg / kg sc at 59 ° / o .

5- [2- (diethylaminoethoxy) -6- [2-diethylaminoethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride at 50 mg / kg sc prolonged survival by 29% in Yshid sarcoma animals .

3.9-dimethyl-5- [2- (diethylamino) ethoxy] -6- (2- (diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride reduced Kr 2 tumor size by 39% at 100 mg dose / kg after and at a dose of 50 mg / kg sc prolonged survival by 35% in animals with Yoshida tumor.

5- (3- (dimethylamino) -2,2-dimethylpropoxy] -6- [3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride elongated at a rate of 100 mg / / kg after survival of animals with HK tumor by 18% and reduced tumor size Kr 2 by 37% / o, the total cell count in ascites decreased by 30% At a dose of 50 mg / kg sc reduced tumor size S 37 by 66% , with the total number of cells in the ascites decreased by 70% and in animals with Yoshida tumor prolonged survival by 42%.

Compounds of formula I in which R ¹ and R ² are as defined above, according to the invention are prepared from compounds of formula IV

(IV) wherein

R ¹ has the abovementioned meaning and M represents sodium or potassium atom condensation with a compound of formula V

Cl- (CH 2) _x -N (R 3) 2 V,

wherein x and R ³ denote the same in formula II or with a compound of formula VI

Cl-CH-C (CH ₃ J2-CH2-N (CH3) 2 VI, wherein the compound of formula V, respectively. VI popžijí in an amount of 2-3 mole equivalents and the actual reaction of the compounds of general formula IV with compounds of formula V and The VI is carried out in an anhydrous medium consisting of an inert solvent, preferably a chlorinated aromatic hydrocarbon, at the boiling point of the solvent used.

Compounds of formula (IV) wherein R ¹ and M are as defined above are prepared from compounds of formula (VII)

replacing hydrogen atoms with alkali metals such as sodium or potassium by conventional non-aqueous methods.

As inert non-aqueous solvent, aromatic hydrocarbons such as benzene, toluene, xylene, higher boiling chlorinated solvents such as dichloroethane, tetrachloroethane, etc. may be used to carry out the reaction. The use of chlorobenzene appears to be particularly advantageous in terms of yield. Etherification and simultaneous esterification of compounds of formula IV with compounds of formula V and formula VI can also be carried out in a two-phase environment, for example a water-immiscible inert solvent - aqueous alkaline hydroxide solution, in the presence or absence of phase transfer catalysts. the solvent may be any of the aforementioned solvents. Carrying out the reaction in these systems does not bring any substantial advantages and appears to be less advantageous in terms of yield.

After the reaction, the reaction mixtures are worked up by the oblique procedures for these types of reactions, for example by extracting the reaction mixture with water and then with a 10% alkali hydroxide solution after completion of the reaction and concentrating the organic layer. The crude reaction product is purified by crystallization from a suitable solvent or solvent mixture and characterized as a base, or more preferably converted by treatment with a 10% excess of a suitable organic or inorganic acid in a lower alcohol, preferably ethanol or methanol, to the corresponding pharmaceutically acceptable a217731 the salt is purified by crystallization from a suitable solvent.

Some inorganic acids, such as hydrochloric, sulfuric, phosphoric and organic acids, such as maleic, tartaric, methane- and ethanesulfonic, napsylic, fumaric, citric and others appear to be suitable acids for the preparation of the editorial salts.

The starting materials for the above reactions, i.e. the compounds of the general formula (VII), are known and readily prepared, for example according to our U.S. Pat. No. 200 094, 202 213, 204 211.

More details about the preparation of compounds of formula I having the above meanings of R ¹ and R ^2, and opřípravě their salts with organic and inorganic acids, will become apparent from the following examples, but should not limit its scope. In the exemplary embodiments, the melting points of the substances are determined on the Kofler block and are not corrected; temperature values are given in degrees Celsius.

Example 1

5- [3- (dimethylamino) -2,2-dimethylpropoxy] -6- [3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H-benzo [c] fluorene

To a solution of sodium methylate prepared by dissolving 0.9 g (0.04 mol) of sodium in 15 ml of methanol is added 50 ml of chlorobenzene and 5.8 g (0.02 mol) of 5-hydroxy-6-carboxy-7-oxo -7H-benzo [c] fluorene and the reaction mixture is gradually heated to boiling point chlorobenzene, while distilling off methanol, then a solution of 5.98 g (0.04 mol) of 3-dimethylamino-2,2- is added to the reaction mixture. dimethylpropyl chloride in 20 ml of chlorobenzene and the reaction mixture was refluxed for 5 hours. After cooling and quenching the reaction mixture with water, the organic layer was separated, extracted with 10% potassium hydroxide solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from benzene to give a melting point of 133-135 °.

Example 2

5- [3- (dimethylamino) -2,2-dimethylpropoxy) -6- (3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride

A solution of 5.16 g (0.01 mol) of 5- [3- (dimethylamino) -2,2-dimethylpropoxy) -6- (3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H -benzo [c] fluorene prepared as described in Example 1 in 30 ml of ethanol is acidified with ethanolic hydrogen chloride solution and, after cooling, the precipitated crystalline solid is filtered off with suction and purified by crystallization from ethanol-chloroform 1: 1. 248 °.

Example 3

In an analogous manner to Examples 1 and 2, the following were prepared:

5- (2- (diethylamino) ethoxy] -6- [2- (dimethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride, m.p. 235-237 ° (ethanol-acetone 2: 1).

5- [2-dienylamino) ethoxy] -6- [diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride; mp 211-213 ° (ethanol)

3.9- Dimethyl 1-5- (2- (diethylamino) ethoxy] -6- [2- (diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride, m.p. 231-232 ° (ethanol- benzene 1: 1).

3.9-diethyl-5- [2- (diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride; mp 236-238 ° (ethanol).

5- (3- (dimethylamino) propoxy) -6- (3- (dimethylamino) propoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride, m.p. 259 DEG-262 DEG (ethanol-tetrachloromethane 1: 1).

Claims (10)

SUBJECT Biologically active basic ethers of 7-oxo-7H-benzo [c] fluorene of the general formula I (II) in which: R ¹ is hydrogen, methyl or ethyl, R ² represents a group of formula II R ³ OF - (CH 2) _X N II, \ R ³ in which R ³ is methyl or ethyl; and x is an integer of 2 or 3, or a moiety of formula III CH3 Z -CH2-C (CH3) _2-CH2 N III \ CH3 and their salts with pharmaceutically acceptable organic and inorganic acids. 2. 5- (2- (dimethylamino) ethoxy] -6- [2- (dimethylamino) ethoxycarbonyl] -7-oxo-7 H -benzo [c] fluorene dihydrochloride. 3. 5- [2- (Diethylamino) ethoxy] -6- [2- (diethylamino) ethoxycarbonyl] -7-oxo-7H-benzo [c] fluorene dihydrochloride. 4. 3,9-Dimethyl-5- [2- (diethylamino) ethoxy] -6 - [(2-diethylaminoethoxycarbonyl) -7-oxo-7H-benzo [c] fluorene dihydrochloride. 5. 3,9-Diethyl-5- [2- (diethylamino) ethoxy] -6- [2-diethylamino) ethoxycarbonyl-7-oxo-7H-benzo [c] fluorene dihydrochloride. 6. 5- (3- (dimethylamino) propoxy) -6- (3- (dimethylamino) propoxycarbonyl] -7-ynyl) -oxo-7H-benzo [c] fluorene dihydrochloride. 7. 5- (3- (dimethylamino) -2,2-dimethylpropoxy) -6- [3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H-benzo [c] fluorene. 8. 5- (3- (dimethylamino) -2,2-dimethylpropoxy) -6- [3- (dimethylamino) -2,2-dimethylpropoxycarbonyl] -7-oxo-7H-benzo [d] fluorene dihydrochloride. 9. A process for the preparation of biologically active basic ethers of 7-oxo-7H-benzo [d] fluorene of the formula I according to claim 1, characterized in that the compound of the formula IV (IV) in which: R ¹ has the same meaning as in formula I and M denotes sodium or potassium, reacts with a compound of formula V Cl - (CH 2) _{x -} N (R ³ ) 2 V in which x and R ³ denote the same as in formula II or with a compound of formula VI Cl - CH 2 - C (CH3) 2-CH2-N _(CH3) 2 VI, whereupon the resulting product, isolated in the base form is converted by neutralization of a pharmaceutically acceptable organic or inorganic acid in an appropriate salt. 10. A process according to claim 9, wherein the reaction of a compound of formula IV with a compound of formula V or VI used in an amount of 2 to 3 mol equivalents is carried out in an inert inert solvent such as a halogenated aromatic hydrocarbon, preferably chlorhenzene. at the boiling point of the reaction mixture.