CS213940B1 - Antineoplastic active derivatives of 7-oxo-7H-benzo [c] fluorene and their production - Google Patents

Abstract

The invention relates to new antineoplastically active derivatives of 7-oxo-7H-benzo[c/ /fluorene of the general formula I 2 í or ethyl group, R denotes a 2,3-epoxypropyl or 1-isopropylamino-2-hydroxy- ! propyl radical. For substances with a basic radical, the subject of the invention are suitable salts with organic or inorganic acids. The substances showed a significant antineoplastic effect in some experimental tumors and leukemia, when evaluated in animals.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to antineoplastic active compounds of the formula I according to claim 1

O / 1 /,

-CH ₂ CH-™

(11) or III

(111) as well as a process for the production of said substances.

The invention also relates to salts of the compounds of formula (I) as defined above in which R represents a group of formula (III) with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula (I), as defined above, have a antineoplastic effect in animals with experimental transplantable vessels and are potential chemotherapeutic agents for human cancer. The compounds were tested in mice with ascitic tumors S 37 and Kr 2, ascitic form of leukemia L 1210, and leukemia La, with mucosal HK tumors and in rats with Yoshid's sarcoma.

In these experiments, the compounds were administered once daily as described below.

For L 1210 and La leukemias, they were given on the days indicated in the respective experiment, in mouse ascitic tumors 8 times on days 1 to 5 and 7 to 9 post-transplant, a similar scheme was chosen for murine solid tumor but starting on day 5 or 7 post-transplant , in rat Yoshida tumor 5x on days 1 to 5 after transplantation. Tumor size was determined the day after the end of administration. Tumor size and survival time were compared to untreated animals.

The following are examples of antitumor activity of some compounds: I-Isopropylamino-3- [5- (7-oxe-7H-benzo [c] fluorenyloxy)] -2-propanol at a dose of 50 mg / kg s.c. reduced tumor size of HK (15%), S 37 (25%) and Kr2 (23%), and prolonged the survival of Yoshida tumor rats by 54%. At a dose of 100 mg / kg p.o. prolonged animal survival, with a Yoshid tumor by 38%.

At a dose of 250 mg / kg s.c. on day 3, prolonged survival of animals with leukemia La by 68% and at a dose of 75 mg / kg s.c. 162%. At a dose of 75 mg / kg p.o. prolonged survival by 88% and at a dose of 250 mg / kg p.o. by 106%.

1- [3-propylamino-3- [5- (3,9-diethyl-7-oxo-7H-benzo [c] fluorenyloxy)] -2-propanol at a dose of 50 mg / kg s.c. reduced the Kr 2 tumor size by 3l% and decreased the total cell count in ascites (total ascitocrit) of the Kr 2 tumor by 29% · In Xoshid sarcoma rats, prolonged survival at the same dose by 43%.

1-Isopropyamino-3- [5- (3,9-dimethyl-7-oxo-7H-benzo [c] fluorenyloxy)] - 2-propanol reduced the tumor size of Kr2 at a dose of 50 mg / kg s.c. by 20% and prolonged the survival of rats with foshid tumor by 30%.

O

Compounds of formula (I) wherein R is as defined above and R is a group of formula (xl) according to the invention are prepared from compounds of formula (IV)

(IV) in which R ¹ is as defined above, with reaction with epichlorohydine, in an environment unsuitable, preferably at lower alconces, in the presence of basicza reactants, in a temperature range of 20 ° C to 4 ° C.

After the reaction, the reaction mixtures are worked up according to conventional methods, for example, after separation of the crude product from the reaction mixture, crystallization or column chromatography is used for purification.

2

Compounds of formula I wherein R is as defined above and R is a group of formula III are prepared according to the invention from compounds of formula I wherein R ¹ has 2

The above meaning of R and R denotes the group of formula II, i.e. the compound of formula V

wherein R is as defined above, by reaction with isopropylamine, in an inert inert aromatic solvent, preferably toluene, in the range of from 50 ° C to the boiling point of the reaction mixture.

After the reaction, the reaction mixtures are worked up in a conventional manner, for example after distilling off the volatiles in a water pump vacuum, the residue is recrystallized or purified by passage through a column of adsorbents in a suitable medium.

Compounds of formula I in which R R has the above exhaust and Ran is a group of formula III are converted into salts by reaction with suitable inorganic or organic acids, of which hydrochloric, phosphoric, tartaric, maleic, napsylová and others. The salt preparation is most preferably carried out in a lower alcohol environment, preferably methanol or ethanol, using the acid and a slight excess (10 to 50%).

LETKA of formula IV of the above meanings of R ¹ are those well known and readily transportable by our CAA. No. 202 213, 204 211, 200 094.

The following examples illustrate the preparation of the compounds of formula (I) and the above-mentioned meanings of R 1 and R ² , but do not limit the scope of the invention. In the exemplary embodiments, the melting points indicated were determined on a Kofler block and are not corrected and refer to crystal free materials.

Example 1

5 - [(2,3) Epoxy] propoxy] -7-oxo-7H-benzo [c] fluorene

To a solution of 1.8 g (0.046 mol) of sodium hydroxide in 40 ml of methanol was added 4.92 g (0.02 mol) of 5-hydroxy-7-oxo-7H-benzo [c] fluorene and the solution was added dropwise. 4.62 g (0.05 mol) of epichlorohydrin and the reaction mixture was allowed to stir at room temperature (20-25 ° C) for 5 days. The product precipitated upon cooling of the reaction mixture is filtered off with suction and, after washing with methanol and drying, recrystallized from chloroform-methanol (2: 1) to give a solid, m.p. Mp 157-158 ° C.

In an analogous manner, prepare:

3.9-dimethyl-5 - [(2,3-epoxy) propoxy] -7-oxo-7H-benzo [a] fluorene, m.p. 183 DEG-185 DEG C. (chloroform-ethanol);

3.9-diethyl-5 - [(2,3-epoxy) propoxy] -7-oxo-7H-benzo [c] fluorene, m.p. 153 DEG -155 DEG C. (chloroform-ethanol).

Example 2 1-Isopropylamino-3- [5- (3,9-diethyl-7-oxo-7h-benzo [c] fluorenyloxy)] - 2-propanol

To a solution of 7.16 g (0.02 mol) of 3,9-diethyl-5- [(2,3-epoxy) propoxy] -7-oxo-7H-benzo [c] fluorene in 50 mL of toluene was added 10 mL ml of isopropylamine and the reaction mixture was refluxed for 6 hours. After evaporation of the volatiles in a water pump vacuum, the crude product was purified by column chromatography using chloroform-benzene (1: 1). By co-crystallization of the combined fractions, a compound of m.p. 144 to 145 ®C.

In an analogous manner, prepare:

l-isopropylamino-3- / 5- (3,9 _'dimethyl-I L-7-oxo-7H-benzo / c / fluorenyl-oxy) -2-propanol,

mp 184-186 ° C (chloroform-ethanol); 1-Isopropylamino-3- [5- (7-oxo-7H-benzo [t] fluorenyloxy) -1,2-propanol, m.p. Mp 156-157 ° C.

Example 3

1-Isopropylamino-3- [5- (7-oxo-7H-benzo [c] fluorenyloxy)] - 2-propanol hydrochloride

To a solution of 4.17 g (0.01 mol) of 1-isopropylamino-3- [5- (7-oxo-7H-benzo [c] fluorenyloxy)] -2-propanol in 30 ml of ethanol is added saturated ethanolic hydrogen chloride solution to pH 4 to 4 and concentrated to crystallize to give the title compound of m.p. Mp 210-212 ° C.

Claims (10)

OBJECT OF THE INVENTION 1. Antineoplastically active derivatives of 7-oxo-7H-benzo (c) fluorene (I): In which R represents a hydrogen atom, a methyl or ethyl group, R represents a group of the formula II - CH3CH - CH3 * V or formula III CH-j -CH2CHCH3NHCH3 OH CH, / 11 /, / 111 /, And salts of the compounds of formula (I), as defined above, in which R represents a group of formula (III), with pharmaceutically acceptable inorganic or organic acids. 2. 5 - [(2,3-Epoxy) propoxy] -7-oxo-7H-benzo [c] fluorene. 3. N 9 -Dimethyl-5 - [(2,3-epoxy) propoxy] -7-oxo-7 H -benzo [c] fluorene. 4. 3,9-Diethyl-5 - [(2,3-epoxy) propoxy] -7-oxo-7H-benzo [c] fluorene. 5. 1-Isopropylamino-3-5- (7-oxo-7H-benzo [t] fluorenyloxy) -2-propanol. 6. 1-Isopropylamino-3- [5- (3,9-dimethyl-7-oxo-7H-benzo [c] fluorenyloxy)] - 2-propanol. 7. 1-Isopropylamino-3- [5- (3'-diethyl-7-oxo-7H-benzo [c] fluorenyl-o-yl) -2-propanol. 8.1? ³ -Isopropylamino-3- [5- (3,9-diethyl-7-oxo-7H-benzo [c] fluorenyloxy)] - 2-propanol, hydrochloride. 9. A process for the production of antineoplastically active 7-oxo-7H-benzo [c] fluorene derivatives of general formula (I). of formula (I) according to item 1, wherein R is as defined above and R * is a group of formula (II), characterized in that the compounds of formula (IV) * (IV) in which R ¹ is as defined above are allowed react with epichlorohydrin in an unsuitable environment, preferably in lower alcohols, in the presence of basic reactants, in a temperature range of from 20 ° C to the boiling point of the reaction mixture. 10. A process for preparing compounds of formula I wherein R ¹ is as defined above and R ² represents a group of formula III according to claim 1, characterized in that the compound of formula I, in which has the abovementioned meaning and R ² denotes 9, reacted with isopropylamine in an inert aromatic solvent, preferably toluene, in a temperature range from 50 ° C to the boiling point of the reaction mixture.