DE2704690A1 - TRIPHENYL ALKENDE DERIVATIVES, MEDICINAL PRODUCTS CONTAINING SUCH, AND METHOD FOR MANUFACTURING THE SAME - Google Patents

Abstract

Triphenylalkene derivatives of the general formula I <IMAGE> in which R is a C1-4-alkyl group and X is a halogen atom, where X has a meaning other than Cl if R is a methyl group, are obtained by dehydrogenation of a triphenyl alkanol derivative of the general formula II <IMAGE> in which R and X have the abovementioned meaning, while R1 and R2 have meanings which differ from one another and designate an H atom or an OH group. The resulting triphenylalkene derivatives inhibit to a considerable extent the growth of the hormone-dependent tumour induced by DMBA.

Description

3description

for patent application relating to triphenylalkene derivatives, containing such Medicaments and Methods for Making Same The invention relates to new ones Triphenylalkene derivatives including their geometric isomers, containing them Medicines, especially those with anti-tumor effects, and a method to manufacture the same.

The 1,2-diphenyl-1- (p-chlorophenyl) -propene- (1) was from G. E. Mousa and coworkers (J. Appl. Chem. 1970, 256) described its biological effectiveness However, it was not investigated. There are also some structurally related ethylene derivatives (Ng. Ph. Buu-Hoi, J. Chem. Soc. 194B, 1080; W. Tadros, J. Chem. Soc. 1949, 439; Ng. Ph. Buu-Hoi, J. Org. Chem. 22 [1957, 1057; A. Boris and co-workers, Arch. Int. Pharmacodyn. 151 01964], 475; H. N. Fox et al., J. Med. Chem. 8 [19652, 250), which by a for the synthesis of alkene derivatives generally applied Method, namely, by removing water (dehydrating) from the appropriate tertiary alkanol derivatives were prepared, known.

The invention relates to triphenylalkene derivatives of the general formula where R stands for an alkyl radical having 1 to 4 carbon atoms and stands for halogen, with the further proviso that, in the case that R stands for the methyl radical, x is different from chlorine, as well as its geometric isomers.

The alkyl radical for which R stands is preferably the ethyl radical.

Furthermore, pharmaceuticals according to the invention, in particular for oral use or parenteral administration, which 1 or more of the compounds of the invention and / or the compound of the formula I in which R represents the methyl radical and X means chlorine Sas means 1,2-I) iphenyl-1- (p-chlorophenyl) - propen- (1), as an active ingredient or active ingredients, optionally together with pharmacologically acceptable contain inert solid or liquid diluents and / or carriers, intended. Those with a content of the [Z] - or EE] -isomers are preferred of the above connections.

The compounds according to the invention and 1,2-diphenyl-1 - (p-chlorophenyl) -propen- ( 1) the medicaments according to the invention have namely, as already mentioned, valuable superior pharmacological, especially anti-tumor properties.

Thus, these compounds inhibit the growth of the DMBA induced hormone-dependent tumor considerably, as has been demonstrated in laboratory animals.

The above compounds are also used as intermediates in their manufacture of the well-known drug used against breast cancer (Z] -1, 2-diphenyl-1p- <2 (dimethylamino) ethoxy> - phenyl} -butene- (1) ETamoxyphene or related compounds (compare the British Patent specifications 1,013,907 and 1,064,629) are useful. 80 can be the first-mentioned connection by reacting a CZ) -1,2-diphenyl-1- (p-halophenyl) -butene- (1) -es according to the invention with 2- (N, N-dimethylamino) ethanol, expediently in the presence of an acid binding By means of being produced.

The invention also relates to a process for the preparation of the compounds according to the invention, which is characterized in that a triphenylalkanol derivative of the general formula is used in a manner known per se where R and X are defined as above and R1 and R2, which are different from one another, represent hydrogen or a hydroxyl group, respectively, is dehydrated and, if appropriate, the isomer mixture obtained is split into its geometric isomers.

Preferably, the dehydration is done with a snake, namely an inorganic acid, in particular hydrochloric acid, hydrobromic acid or phosphoric acid, or organic acid, in particular trifluoroacetic acid or formic acid. Mixtures of acids can also be used.

It is also preferred to carry out the reaction in an inert diluent or solvents, in particular an optionally aqueous alcohol, to be carried out.

The separation of the isomer mixture of the relevant he inventive Triphenylalkeneivates can be advantageous by crystallizing from an organic Lögunemltte] or solvent mixture can be carried out.

The cleavage of the isomer mixture obtained is expedient into the [Z3 and UE0 isomers by fractional crystallization from an organic Solvent or solvent mixture or carried out by chromatography.

Those used as starting materials in the process according to the invention new triphenylalkanol derivatives of the formula II can in a manner known per se, for example by converting bromobenzene with magnesium into phenylmagnestum bromide and reacting the latter with the appropriate 4-halo-d-alkyldeoxybenzoin and hydrolytic decomposition of the Grignard complex obtained or by transferring it of the appropriate 4-halobromobenzene with magnesium into the corresponding 4-halophenylmagnesium bromide and reacting the latter with the appropriate o (-alkyldeoxybenzoin and hydrolytic Decomposition of the Grignard complex obtained, the 4-halogen - «- alkyldeoxybenzoin by reacting the appropriate 4-Halogendeso% ybenzoines with sodium and the appropriate Alkyl iodide may have been obtained.

The invention is explained in more detail by means of the following examples.

Example 1 A solution of 135.0 g (0.355 mol) of 1,2-diphenyl-1- (p-bromophenyl) -butan-1-ol in 1,400 cm3 of ethanol with 300 cm3 of 36% above hydrochloric acid to boiling for 5 hours heated. After distilling off the alcohol in vacuo, the aqueous residue became with 1,500 cm3 of methylene chloride or dichloromethane in several proportions extracted and the organic phase with water until it is neutral Reaction washed and then dried. After the solvent has been distilled off the crystalline crude product was recrystallized from ethanol, whereby 120.0 g (93% of theory) 1,2-diphenyl-1 - (p-bromophenyl) -butene- (1) with a melting point of 64 to 82 ° C and a ratio of the [Z isomer to the LE) isomer of 1: 1 became.

After this product has been recrystallized 3 times from isopropanol the LZ] isomer with a melting point of 112 to 1150C was obtained.

After the mother liquor has been evaporated to dryness and recrystallized twice of the residue from methanol became the [EJ isomer with a melting point of 89 received up to 920C.

The 1,2-diphenyl-1 - (p-bromophenyl) -butan-1-ol used as the starting substance was obtained as follows: A solution of 20.6 g (0.90 mol) of sodium was obtained in 600 cm3 of anhydrous alcohol with 165.0 g (0.60 mol) of 4-bromodeoxybenzoin (I. L. Kotlyarevskii and N. I. Popova, Izv. Akad. Nauk SSSR, Ser. Khin. 1967, 208) implemented. The cooled solution was added with 140.0 g (0.90 mol) of ethyl iodide united and then heated to boiling for 5 hours. The reaction mixture was poured into ice water poured in and that which separated out as oil and then solidified in a few hours Product was filtered off and dried. The 4-bromo-4-ethyldeoxybenzoin obtained was purified by distillation. Yield: 155.5 g (85.5% of theory); SchTnel7, -punkt: 50 to 530C; Boiling point: 173 to 1800C / 0.7 Torr.

Then 14.6 g (0.60 mol) of magnesium in 600 cm3 of anhydrous ether with stirring or shaking with a solution of 94.2 g (0.60 mol) of bromobenzene implemented in 100 cm3 anhydrous ether. To the cooled solution of the resulting Grignard reagent was a solution of 151.5 g (0.50 mol) of 4-bromine - «- ethyl deoxyrbenzoin in 300 cm3 of anhydrous ether was added and the mixture was stirred for 1 hour Boiling heated. 600 cm3 of 1.0 N hydrochloric acid were added to the cooled reaction mixture added 1md the organic phase was separated. The aqueous phase was repeated several times extracted with ether, whereupon the combined ethereal phases with a 10% Solution of ammonium chloride and shaken with water and then dried. After the solvent had been distilled off, the crystalline crude product became out 90% ethanol recrystallized.

152.0 g (79.6% of theory) of 1,2-diphenyl-1 - (p-bromophenyl) butan-1-ol were thus obtained obtained with a melting point of 138 to 1400C.

Example 2 A solution of 320.0 g (1.0 mol) of 1,2-diphen, yl - 1- (p-fluorophenyl) -butan-1-ol in 3 800 cm3 ethanol with 850 cm3 of the above hydrochloric acid for 1 hour to the boil heated. After suctioning off the cooled solution retired They were crystals with several proportions of water until they reached neutral Reaction washed.

When the mother liquor was concentrated to half its volume, another Received part of the product. After recrystallization of the crude product (290 g) 90% ethanol became an isomer mixture of 1,2-diphenyl-1- (p-fluorophenyl) -butene-(1) -es in a yield of 257.0 g (84.9% of theory) with a melting point of 65 to 700C and a ratio of the (ZJ isomer to the [E) isomer of 1: 1. This isomer mixture was on a silica gel column impregnated with silver nitrate, whose silica gel had a grain size of 0.063 to 0.20 mm by eluting with a non-polar solvents (e.g. petroleum ether or cyclohexane) into its isomers split. From 5 g of the isomer mixture, 2.46 g (49.3% of theory) of the [Z | isomer were obtained with a melting point of 77 to 80 ° C. and 1.21 g (24.2% of theory) of the (E3 isomer obtained with a melting point of 78 to 81 0C.

The 1,2-diphenyl-1 - (p-fluorophenyl) -butan-1-ol used as the starting substance was obtained as follows: A solution of 29.2 g (1.20 mol) of magnesium was obtained in 150 cm3 anhydrous ether while stirring or shaking with a Solution of 210.0 g (1.20 mol) of 1-bromo-4-fluorobenzene in 420 cm3 of anhydrous ether implemented, whereupon the solution after cooling, a solution of 224.3 g (1.0 mol) α-Ethyldeoxybenzoin (T. E. Zalleskajn and O. A. Netsetskaja, Sh. Org.Khim. 5 [1969], 1 076) in 1,000 cm3 of ether was added. The reaction mixture was Heated to the boil for 4 hours, then cooled and mm 1 000 cm3 of a 10% strength Ammonium chloride solution added.

The ethereal phase was separated and then the aqueous phase extracted with further portions of ether.

The combined ethereal phases were evaporated to dryness. The 314.0 g (98% of theory) of crystalline 1,2-diphenyl-1- (p-fluorophenyl) -butan-1-ol thus obtained with a melting point of 80 to 88 ° C could without further purification to 1,2-diphenyl-1- (p-fluorophenyl) -butene- (1) implemented. After recrystallization from 90% ethanol, it had 1,2-diphenyl-1- (p-fluorophenyl) -butan-1-ol a melting point of 94 to 96 ° C.

Example 3 A solution of 33.70 g (0.10 mol) of 1,2-diphenyl-1- (p-chlorophenyl) -butan-1-ol was obtained Boiled in 400 cm3 of ethanol with 85 cm3 of its own hydrochloric acid for 2 hours.

The solution was cooled and the precipitated crystals became all filtered off, washed with water and then recrystallized from 90% ethanol. So was an isomer mixture of 1,2-diphenyl-1- (p-chlorophenyl) -butene- (1) in one Yield of 28.3 g (88.8% of theory) with a melting point of 67 to 80 ° C. and a ratio of the [Z) isomer to the [El isomer of 1: 1.

The 1,2-diphenyl-1 - (p-chlorophenyl) butan-1-ol used as the starting material has been produced as follows: 4.38 g (0.18 mol) of magnesium in 25 cm3 w: r1s "for free ether with stirring or shaking with a solution of 34.4 g (0.18 mol) of 1-bromo-4-chlorobenzene reacted in 70 cm3 of anhydrous ether, whereupon the cooled solution a solution of 33.6 g (0.15 mol) of α-ethyldeoxybenzoin in 140 cm3 of anhydrous ether added and the mixture to boiling for 4 hours was heated. Then the cooled mixture was mixed with an ammonium chloride solution offset, the ethereal phase separated and the aqueous phase shaken out with further portions of ether. After distilling off the Crystalline crude product obtained from solvent was recrystallized from alcohol, whereby 44.0 g (87.1% of theory) 1,2-diphenyl-1- (p-chlorophenyl) - butan-1-ol with a melting point of 109 to 111 ° C were obtained.

Claims

Claims (7)

Patent claims triphenylalkene derivatives of the general formula where R stands for an alkyl radical having 1 to 4 carbon atoms and X stands for halogen, with the further proviso that, in the case that R stands for the methyl radical, X is different from chlorine, as well as its geometric isomers. 2.) triphenylalkene derivatives according to claim 1, characterized in that that the alkyl radical for which R stands is the ethyl radical. 3.) Medicines, characterized by a content of 1 respectively several compounds according to claim 1 or 2 and / or the compound of the formula #, in which R stands for the methyl radical and X stands for chlorine, as an active ingredient in relation to each other Active ingredients, if necessary together with pharmacologically acceptable inert ones solid or liquid thinners and / or carriers. 4.) Process for the preparation of the compounds according to claim 1 or 2, characterized in that a triphenylalkanol derivative of the general formula is used in a manner known per se where R and X are defined as in claim 1 or 2 and R1 and R2, which are different from one another, represent hydrogen or a hydroxyl group, respectively, are dehydrated and, if appropriate, cleavage of the isomer mixture obtained into its geometric isomers. 5.) The method according to claim 4, characterized in that man dehydration with an acid, especially hydrochloric acid, hydrobromic acid, Phosphoric acid, trifluoroacetic acid or formic acid. 6.) Method according to claim 4 or 5, characterized in that the reaction in an inert diluent or solvent, in particular an, optionally aqueous, alcohol is carried out. 7.) Process according to claim 3 to 5, characterized in that one the splitting of the obtained isomer mixture into the Iz] and tE] isomers by fractionated Crystallizing from an organic solvent or solvent mixture, or carried out by chromatography.