Terpene-quinones with antitumour activity

Details Terpene-quinones with antitumour activity Terpene-quinones with antitumour activity

1996-10-04

1998-04-28

Reamer, James H.

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclohexadiene having atoms double bonded directly at the 1-...

552298, 552299, 568609, 568736, C07C22100

Patent

active

057446237

DESCRIPTION:

BRIEF SUMMARY
Present document relates to the developement of a series of novel products such as a new series of terpene-quinones, as well as the procedure for its obtention.
Avarol and its quinone analogue, avarone are mero-sequiterpenoids isolated from a sponge, Dysidea avara, which showed certain cytotoxic activity and which can be considered as a model for a series of analogous, yet discovered or prepared afterwards, containing different variants of substitution at the quinone portion and/or the chain at the sesquiterpene portion. A good number of these compounds containing a bicyclic serterpene system posess cytotoxic activity with values of IC.sub.50 arround 1 microgram per millilitre. Other sesquiterpene-quinones with monocyclic terpene groups have also similar levels of activity.
Up to date, there has not been published any study on the structure-activity relationship of these compounds regarding to size and type of quinone and terpene groups of the molecule. Therefore, in this work it has been aimed to analyze the effect of the increase, diminution and functionalization of terpene group and the expansion of quinone nucleus up to naphthoquinone.
In order to realize a clear exposition of the processes of the invention, it will be attached to this text those reactions which are going to be explained hereinafter, written as their chemical formulae, said reactions resulting the invention's generic ones.
The molecules which are the objective or this work comprise a simple or substituted type A naphthoquinone as quinone system, in which R.sup.1 is an alkyl or alkoxy group and T matches an alkyl or cycloalkyl group, prefferably of isoprene, monoterpene, sesquiterpene type or with an intermediate size between these types. ##STR1##
Likewise, there are included as an objective those naphthoquinone derivatives of types B and C and the corresponding dihydroxynaphthalene analogous of types D and E.
Most of these compounds have been synthetized by using the Diels-Alder cyclocondensation, as a base-reaction, between conveniently substituted p-benzoquinone and a compound comprising a conjugated diene system, in the presence of a catalyst or not. The further Manipulation, equilibration or chemical modification of the directly resulting cycloaddition product (B) can successively yield the compounds of types E, C, D and A which are represented below for two different kinds of diene system substitution.
This first kind of diene system substitution is shown in its reaction as follows: ##STR2##
The second kind of diene system substitution fore mentioned will be: ##STR3##
Starting compounds, useful for cycloadditions, have a conjugated diene system along carbon chains of the linear or branched alkane: 2,6-dimethyloctane, 2,6,10-trimethyldodecane, 2,6,10,14-tetramethylhexanedecane, 2,6,10,15,19,23-hexamethyltetracosane or on any other of a cyclical nature biogenesically or artificially related to these.
Chemical names of those kinds of compounds refered in said generic reactions will be the following, taking into consideration that in said names there will appear numbers and words in brackets, meaning possible positions for a substituent and the possibility for said function or structural modification to exist, respectively, and that they will be included in subtypes, depending on R.sup.1 and T:


TYPE A COMPOUND

R.sup.1 =Hydrogen 5(6)-alkyl(alkenyl)-naphtho-1,4-quinones 5(6)-(poly)cycloalkyl(cycloalkenyl)-alkyl-naphtho-1,4-quinones 5(6) -(poly)cyclo(poly)isoprenyl-naphtho-1,4-quinones
R.sup.1 =Alkyl 2(3)-alkyl-5(6)(7)(8)-alkyl(alkenyl)-naphtho-1,4-quinones 2(3)-alkyl-5(6)(7)(8)-(poly)cycloalkyl(cycloalkenyl)-alkyl-naphtho-1,4-qui nones 2(3)-alkyl-5(6)(7)(8)-(poly)cyclo(poly)isoprenyl-naphtho-1,4-quinones
R.sup.1 =Alkoxy 2(3)-alkoxy-5(6)(7)(8)-alkyl(alkenyl)-naphtho-1,4-quinones 2(3)-alkoxy-5(6)(7)(8)-(poly)cycloalkyl(cycloalkenyl)-alkyl-naphtho-1,4-qu inones 2(3)-alkoxy-5(6)(7)(8)-(poly)cyclo(poly)isoprenyl-naphtho-1,4-quinones
R.sup.1 =(di)Alkylamine 2(3)-(di)Alkylamine-5(6)(7)(8)-alkyl(alkenyl)-naphtho-1,4-quinones 2(3) -(di)Alkyla

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