Patent Application: US-201013383563-A

Abstract:
the present invention relates to the synthesis of novel biologically active selenoquinone - derived organometallic complexes , and to the uses thereof in the context of preventing or treating cancer .

Description:
the inventors of the present invention have unexpectedly developed a novel synthetic process which is reliable , inexpensive , reproducible and easy to carry out , which makes it possible to obtain first stable organometallic complexes derived from selenoquinone . they also discovered , entirely unexpectedly , that these complexes , which until now had not been isolated or characterized , exhibit biological ( cytotoxicity ) properties at least equivalent to those of cisplatin , for this reason making it possible to use them in the context of the prevention or treatment of diseases involving abnormal cell proliferation , in particular cancer . the term “ stable ” is preferably understood to mean complexes which are sufficiently stable to allow them to be prepared and which remain intact for a period of time sufficient to allow them to be detected and preferably for a period of time sufficient to be able to be used in the context of the prevention or treatment of diseases involving abnormal cell proliferation , in particular cancer . the term “ abnormal cell proliferation ” is understood to mean a proliferation which is independent of the normal regulating mechanisms , for example the halting of cell proliferation due to the involvement of apoptosis ( programmed cell death ). the present invention thus relates firstly to an isolated organometallic compound of general formula ( i ): ( c 5 me 5 ) m ( η 4 - c 6 e 1 e 2 r 3 r 4 r 5 r 6 ) ( i ) m represents a metal ru , co , rh or ir ; e 1 represents an oxygen , sulfur or selenium atom ; e 2 represents a selenium atom ; r 3 , r 4 , r 5 and r 6 represent , independently of one another , a hydrogen atom , a hydroxyl group , a c 1 - 8 alkyl group , a c 2 - 8 alkenyl group , a c 2 - 8 alkynyl group , a c 1 - 6 alkoxyl group , a c 6 - 14 aryl group or an r ′— nh amine group where r ′ represents a hydrogen atom , a c 1 - 8 alkyl group , a c 2 - 8 alkenyl group or a c 2 - 8 alkynyl group . the term “ isolated ” is generally understood to mean a compound which is ( i ) separated from at least one compound with which it is associated naturally and / or ( ii ) produced , prepared or manufactured by the hand of man . the term “ η 4 ” is understood to mean the “ hapticity of 4 ”, that is to say that the arene is bonded to the metal via four bonds . the alkyl groups can comprise from 1 to 8 carbon atoms , preferably from 1 to 6 carbon atoms and in particular from 1 to 2 carbon atoms . the alkenyl groups can comprise from 2 to 8 carbon atoms , preferably from 2 to 6 carbon atoms and in particular from 2 to 4 carbon atoms . in addition , they can comprise one or more double bond ( s ). the alkynyl groups can comprise from 2 to 8 carbon atoms , preferably from 2 to 6 carbon atoms and in particular from 2 to 4 carbon atoms . in addition , they can comprise one or more triple bond ( s ). the alkoxyl groups can comprise from 1 to 6 carbon atoms , preferably from 1 to 4 carbon atoms and in particular from 1 to 2 carbon atoms . the aryl groups denote a mono -, bi - or tricyclic hydrocarbon system comprising one , two or three rings satisfying the huckel aromaticity rule . for example , an aryl radical can be a phenyl , naphthyl , tetrahydronaphthyl , indanyl or indenyl group and similar radicals . the aryl groups can comprise from 6 to 14 carbon atoms and in particular from 6 to 10 carbon atoms . unless otherwise mentioned , the alkyl , alkenyl , alkynyl or alkoxyl groups can be linear , branched or cyclic . according to the present invention , e 1 and e 2 each represent a selenium atom and r 3 , r 4 , r 5 and r 6 are as defined above ; preferably , at least one of them represents a c 1 - 8 alkyl group , very preferably a methyl group . for example , e 1 and e 2 each represent a selenium atom , r 3 and r 5 each represent a hydrogen atom and r 4 and r 6 each represent a methyl group . according to the present invention , e 1 and e 2 each represent a selenium atom and r 3 , r 4 , r 5 and r 6 each represent a hydrogen atom . according to the present invention , e 1 represents a sulfur or oxygen atom , preferably an oxygen atom , e 2 represents a selenium atom and r 3 , r 4 , r 5 and r 6 each represent a hydrogen atom . according to the present invention , in organometallic complexes of the present invention , e 1 and e 2 are in the ortho - or para - position . according to the present invention , said complexes have one of the following structures : in addition , the inventors have demonstrated that the organometallic complexes of the present invention have biological ( cytotoxicity ) properties at least equivalent to those of cisplatin . thus , according to a specific embodiment of the present invention , the organometallic complexes of the present invention can be used as medicament , in particular for the production of a medicament intended for the treatment of cancer . the organometallic complexes of the present invention can , if appropriate , be in the salt solvated form or in the form of other physiologically acceptable derivatives . the salts and the solvents which are acceptable for pharmaceutical use are generally those in which the associated counterion or solvent is pharmaceutically acceptable . the salts which can be used can be organic or inorganic acids or bases . mention may be made , among acceptable acid addition salts , of those formed from hydrochloric , hydrobromic , sulfuric , citric , tartaric , phosphoric , lactic , pyruvic , acetic , trifluoroacetic , phenylacetic or triphenylacetic acid . mention may also be made , among acceptable basic salts , of salts of alkali metals , such as sodium or potassium , salts of alkaline earth metals , such as calcium and magnesium , and salts formed from organic bases , such as mono -, di - or trisubstituted amines . the present invention also relates to a pharmaceutical composition comprising , as active principle , at least one compound according to the present invention in a pharmaceutically acceptable vehicle . in the pharmaceutical composition , the compounds are employed in an effective amount . this will be determined by a person skilled in the art according to various parameters , in particular with respect to the substance used , the age , weight and physical condition of the patient , the method of administration and the regime required . a person skilled in the art will be in a position to determine the method of administration and the dosage for each patient . very particularly , the compound according to the invention can be administered at a dose ranging from 0 . 1 to 5000 mg per day and per patient . the pharmaceutical composition can comprise an amount of compound according to the invention ranging from 0 . 1 mg to 5 g . the pharmaceutical composition can be administered in any topical or systemic form , in particular in the parenteral or enteral form . when the composition or the medicament is administered by the enteral route , it can be provided in the form of tablets , including sugar - coated tablets , hard gelatin capsules , syrups , suspensions , solutions , powders , granules , emulsions or microspheres . in the case of administration by the parenteral route , the composition can be provided in the form of solutions or suspensions for infusion or for injection . in addition , the composition can comprise at least one additive chosen in particular from coloring agents , flavoring agents and preservatives . of course , a person skilled in the art will take care to choose the additive or additives so that the advantageous properties intrinsically attached to the invention are not , or not substantially , detrimentally affected by the envisaged addition . according to a specific embodiment , the composition according to the invention can additionally comprise another compound intended to treat cancer . mention may be made , among the compounds which can be used according to the invention , of doxorubicin , the commercial name of which is adriamycin ®, epothilone , paclitaxel , the commercial name of which is taxol ®, and cisplatin . according to yet another of its aspects , the subject matter of the invention is the use of at least one organometallic complex of the present invention in the preparation of a pharmaceutical composition intended to treat and / or prevent a disease involving abnormal cell proliferation , in particular a cancer . said composition can be intended for human and / or veterinary medicine and it can in particular be intended to treat or prevent at least one cancer chosen , for example , from pancreatic cancer , oropharyngeal cancer , stomach cancer , esophageal cancer , colorectal cancer , brain cancer , in particular gliomas , ovarian cancer , liver cancer , kidney cancer , laryngeal cancer , thyroid cancer , lung cancer , bone cancer , multiple myelomas , mesotheliomas and melanomas , skin cancer , breast cancer , prostate cancer , bladder cancer , uterine cancer , testicular cancer , non - hodgkin &# 39 ; s lymphoma , leukemia , hodgkin &# 39 ; s disease and soft tissue cancers , as well as secondary metastatic occurrences of the abovementioned cancers . the present invention also relates to a process for the synthesis of the organometallic complexes of the present invention which comprises a nucleophilic attack on the compound of following formula ( ii ): [( c 5 me 5 ) m ( η 6 - c 6 x 1 x 2 r 3 r 4 r 5 r 6 )][ z ] 2 ( ii ) m , r 3 , r 4 , r 5 and r 6 are as defined above ; x 1 and x 2 are identical or different and each represent a halogen atom cl , br or i ; z represents a counteranion bf 4 − , pf 6 − or cf 3 so 3 − ( or otf − ), by at least one nucleophile y 2 se , where y is an alkali metal cation . according to a specific embodiment of the synthetic process of the present invention , the nucleophilic attack is carried out with sodium selenide ( na 2 se ). other advantages may further appear to a person skilled in the art on reading the following examples , illustrated by the appended figures , given by way of illustration . fig1 represents the crystallographic structure of the organometallic complex [( c 5 me 5 ) ir ( η 4 - p - diselenobenzoquinone )] ( 8 ). three different synthetic processes exist for preparing quinone complexes ( 1 - 4 ), dithioquinone complexes ( 5 , 6 ) and mono - and diselenoquinone complexes ( 7 , 8 , 9 , 10 ). the synthesis of the families 1 - 6 is well known in the art [ 13 ], in contrast to that of the mono - and diselenoquinone complexes , which constitutes a subject matter of the present invention . para - quinone organometallic complexes were prepared by direct treatment of hydroquinone and the solvated compound [( c 5 me 5 ) m ( solvent ) 3 ] 2 + , where m = rh or ir , prepared in situ , followed by a subsequent deprotonation by a base , in order to obtain the para - quinone organometallic complexes p -[( c 5 me 5 ) m ( η 4 - quinone )], where m = rh ( 2 ) or ir ( 4 ) [ 8 - 9 ]. similarly , ortho - quinone organometallic complexes were obtained by treatment of catechol with the solvated compound [( c 5 me 5 ) m ( solvent ) 3 ] 2 + , where m = rh or ir , in the presence of bf 3 . 2h 2 o as activator of the arene , in order to provide for the bonding of the metal fragment to the arene ring , followed by a deprotonation , in order to obtain the ortho - quinone organometallic complexes o -[( c 5 me 5 ) m ( η 4 - quinone )], where m = rh ( 1 ) or ir ( 3 ) [ 11 ]. the sulfur homologs of hydroquinone and catechol were obtained by a different synthetic process from above . thus , the air - sensitive ortho - and para - dichlorobenzene organometallic complexes were prepared and isolated in the form of white microcrystalline compounds . a treatment of said compounds with sodium hydrosulfide produced the thioquinone organometallic complexes in the form of ortho -( 5 ) and para -( 6 ) isomers [ 12 ]. 3 — synthesis of the iridium / mono - and diselenoquinone complexes ( 7 , 8 , 9 , 10 ) the ortho - and para - selenoquinone organometallic complexes were synthesized according to the following reaction scheme : the first stage of this synthetic scheme involves the preparation of air - sensitive halogenated organometallic complexes of ortho - and para - dichlorobenzene [( c 5 me 5 ) ir ( η 6 - c 6 h 4 cl 2 )][ bf 4 ] 2 , air - sensitive halogenated organometallic complex of para - monochlorohydroxybenzene p -[( c 5 me 5 ) ir ( η 6 - c 6 h 4 cloh )][ bf 4 ] 2 and air - sensitive halogenated organometallic complex of para - dichlorodimethylbenzene p -[( c 5 me 5 ) ir ( η 6 - c 6 h 2 cl 2 ( ch 3 ) 2 )][ bf 4 ] 2 . 3 - 1 — synthesis of the complex p -[( c 5 me 5 ) ir ( η 4 - diselenobenzoquinone )] ( 8 ) a colored solution of p -[( c 5 me 5 ) ir ( η 6 - c 6 h 4 cl 2 )][ bf 4 ] 2 ( 340 mg , 0 . 52 mmol ) in ch 3 cn distilled at the time of use ( 10 ml ) was added to a schlenk tube containing anhydrous na 2 se ( 650 mg , 5 . 2 mmol ) stored under an argon atmosphere . the reaction mixture rapidly changed to orange in color with the formation of a precipitate ( nacl and nabf 4 ). the reaction was maintained for 20 minutes and then the solvent was removed under vacuum in order to provide an orangey black residue . subsequently , the compound was extracted using 50 ml of distilled ch 2 cl 2 and filtered under an argon atmosphere through a sintered glass filter equipped with cotton wool / celite / cotton wool to give a bright orange color . the solvent was removed under vacuum to give an orange microcrystalline powder identified as p -[( c 5 me 5 ) ir ( η 4 - c 6 h 4 se 2 )][ bf 4 ] 2 ( 241 mg , 0 . 49 mmol ). yield 95 %. the compound ( 8 ) is stable and can be stored for a long period under an argon atmosphere . the compound ( 8 ) is soluble in ch 2 cl 2 , meoh and acetone and in the majority of polar organic solvents . ir ( atr ), ν cm − 1 : 2990 , 1467 , 1421 , 1380 , 1272 , 1053 , 1024 , 731 , 704 , 633 , 431 , 353 . 1 h nmr ( 400 mhz , cd 2 cl 2 ), δ ( ppm ): 1 . 89 ( 15h , s , η - c 5 me 5 ); 6 . 26 ( 4h , s , ch p - diselenobenzoquinone ). 13 c { 1 h } nmr ( 100 mhz , cd 2 cl 2 ), δ ( ppm ): 6 . 86 ( ch 3 , s , η - c 5 me 5 ); 96 . 83 ( ch , s , p - diselenoquinone ); 96 . 97 ( c ═ c , s , η - c 5 me 5 ); 132 . 96 ( c — se , s , diselenoquinone ). 77 se { 1 h } nmr ( 400 mhz , cd 2 cl 2 ), δ ( ppm ): 296 ( 2se , s , c — se ). 3 - 2 — synthesis of the complex o -[( c 5 me 5 ) ir ( η 4 - diselenobenzoquinone )] ( 7 ) the compound ( 7 ) was prepared in a similar way to that of the compound ( 8 ). the molecule is somewhat less stable than the para - isomer . studies are currently underway to optimize the method of synthesis . ir ( atr ), ν cm − 1 : 3373 , 2912 , 1585 , 1467 , 1378 , 1258 , 1019 , 885 , 800 , 728 , 696 , 636 , 608 , 550 , 518 , 464 , 386 , 308 . 3 - 3 — synthesis of the complex p -[( c 5 me 5 ) ir ( η 4 - monoselenobenzoquinone )] ( 9 ) the compound ( 9 ) was prepared in a similar way to that of the compound ( 8 ) but starting from the monochlorinated organometallic complex p -[( c 5 me 5 ) ir ( η 6 - c 6 h 4 cloh )][ bf 4 ] 2 and was obtained with a yield of 90 %. 1 h nmr ( 400 mhz , cd 2 cl 2 ) δ ( ppm ): 1 . 92 ( 15h , s , η - c 5 me 5 ); 5 . 32 ( 2h , d , 6 hz , ch p - diselenobenzoquinone ); 6 . 29 ( 2h , d , 6 hz , ch p - diselenobenzoquinone ). ir ( atr ), ν cm − 1 : 2964 , 2917 , 1630 , 1605 , 1468 , 1385 , 1259 , 1024 , 802 , 691 , 636 , 606 , 557 , 518 , 452 , 429 . 3 - 4 — synthesis of the complex p -[( c 5 me 5 ) ir ( η 4 - 2 , 5 - dimethyldiselenobenzoquinone )] ( 10 ) the compound ( 10 ) was prepared in a similar way to that of the complex ( 8 ) but starting from p -[( c 5 me 5 ) ir ( η 6 - c 6 h 2 cl 2 ( ch 3 ) 2 )][ bf 4 ] 2 and was obtained with a yield of 90 %. 1 h nmr ( 400 mhz , d 4 - meoh ), δ ( ppm ): 1 . 79 ( 15h , s , η - c 5 me 5 ); 2 . 51 ( 6h , s , ch 3 —); 6 . 78 ( 2h , s , ch p - diselenobenzoquinone ). ir ( atr ), ν cm − 1 : 3616 , 3568 , 1637 , 1467 , 1406 , 1381 , 1259 , 1043 , 893 , 742 , 634 , 606 , 522 , 461 . biological properties of the quinone , thioquinone and selenoquinone organometallic complexes ( 1 - 10 ) the biological ( cytotoxicity ) properties of the complexes synthesized above were tested on a2780 and a2780cisr ( cisplatin - resistant ) ovarian cancer cells according to a conventional procedure described below , and the ic 50 values obtained were compared with those obtained under the same conditions with the cisplatin complex pt ( nh 3 ) 2 cl 2 . the a2780 and a2780cisr ovarian cancer cell lines were obtained from the european collection of cell cultures ( ecacc ) ( salisbury , uk ). the cells were cultured in rpmi medium comprising glucose , 5 % of fetal calf serum ( fcs ) and antibiotics , at 37 ° c . and 5 % co 2 . the cytotoxicity was determined using the mtt ( 3 -( 4 , 5 - dimethyl - 2 - thiazolyl )- 2 , 5 - diphenyl - 2h - tetrazolium bromide ) test ( mosmann , 1983 ). the cells were distributed in 96 - well plates , as monolayers , with 100 μl of solution ( approximately 20 000 cells ) per well , and were preincubated for 24 hours in a medium supplemented with 10 % of fcs . the compounds were prepared in dmso solution , were then dissolved in the culture medium and were successively diluted to the appropriate concentration , in order to obtain a final dmso concentration of 0 . 5 %. 100 μl of solution of these compounds were added to each well and the plates were incubated for 72 hours . subsequently , mtt ( 5 mg / ml ) was added to the cells and the plates were incubated for 2 hours . the culture medium was removed by suction and the purple formazan crystals formed by the mitochondrial dehydrogenase activity of the living cells were dissolved in dmso . the optical density , which is directly proportional to the number of living cells , was quantified at 540 nm using a multiwell plate reader and the fraction of living cells was quantified from the absorbance of untreated control cells . evaluation was carried out from two independent experiments , each comprising 3 microcultures per concentration level . the ic 50 values obtained are presented in table 1 below . the results show that the dithiobenzoquinone complexes and in particular the monoselenoquinone and diselenoquinone organometallic complexes ( 8 - 10 ) have significant biological ( cytotoxicity ) properties equivalent to those of the cisplatin compound with regard to the a2780 ovarian cancer cell line . in addition , in an entirely noteworthy way , the two complexes 9 and 10 have superior cytotoxic properties to cisplatin with regard to the a2780cisr ( cisplatin - resistant ) ovarian cancer cell line , with an ic 50 value of 8 . 4 μmol for compound 9 and an ic 50 value of 7 . 3 μmol for compound 10 , whereas the ic 50 value of the cis -[ pt ( nh 3 ) 2 cl 2 ] complex for the a2780cisr cell line is 25 μmol . the organometallic complexes of the invention can thus be used in the context of the prevention and / or treatment of diseases involving abnormal cell proliferation , in particular cancer . their use will be very particularly beneficial in the context of diseases for which a treatment based on cisplatin has proved to be not very effective or indeed even ineffective . crystallography of the diselenobenzoquinone complex p -[( c 5 me 5 ) ir ( η 4 - diselenobenzoquinone )] ( 8 ) crystals of the biologically active molecule [( c 5 me 5 ) ir ( η 4 - p - diselenobenzoquinone )] ( 8 ) were obtained by slow diffusion of ethyl ether into a methanol solution of this complex . x - ray diffraction made it possible to resolve the structure . to do this , the structure was resolved by direct methods using the sir92 program [ 18 ] and refined anisotropically by the full matrix least squares method using the shelxl - 97 software package [ 19 ]. the structure resolved by x - ray diffraction ( fig1 ) shows that this complex crystallizes in a monoclinic mesh with the p2 1 / c space group and z = 4 . the analysis of the distances and angles [ table 2 : selection of distances ( å ) and angles ) (°)] made it possible to confirm the formation of the p - diselenobenzoquinone . this data indicated that the p - diselenobenzoquinone is coordinated to the iridium via the 4 diene carbon atoms c ( 2 ), c ( 3 ), c ( 5 ) and c ( 6 ). this is because the ir ( 1 )- c ( 1 ) and ir ( 1 )- c ( 4 ) distances are longer than the ir ( 1 )- c ( 2 ), ir ( 1 )- c ( 3 ), ir ( 1 )- c ( 5 ) and ir ( 1 )- c ( 6 ) distances . consequently , the p - diselenobenzoquinone has adopted a conformation slightly angled in the boat form . the dihedral angle between the [ c ( 2 ) c ( 3 ) c ( 5 ) c ( 6 )] and [ c ( 2 ) c ( 1 ) c ( 6 )] planes is equal to 7 . 04 °. that between the [ c ( 2 ) c ( 3 ) c ( 5 ) c ( 6 )] and [ c ( 3 ) c ( 4 ) c ( 5 )] planes is equal to 5 . 94 °. in addition , the c ( 1 )- se ( 1 ) and c ( 4 )- se ( 2 ) distances are equal to 1 . 876 å and 1 . 865 å respectively . these distances are in agreement with a double rather than single nature for the bond between c and se in comparison with the c — se distance found for se — ar ( 1 . 925 å ) [ 16 ] and the c ═ se distance ( 1 . 88 å ) [ 17 ] encountered in the cobalt complex [ cocl 2 ( c 5 h 8 n 2 se ) 2 ]. furthermore , the examination of the structure at the level of the crystal showed that this complex forms stacks by π - π interactions between the molecules of the [( c 5 me 5 ) ir (( η 4 - c 6 h 4 se 2 )]. furthermore , the aromatic ring of the cp * ligand interacts with the diene system of the p - diselenobenzoquinone of a neighboring molecule ( d = 3 . 563 å ). these interactions make possible the formation of a supramolecular chain , the cohesion of which is provided by the π - π stackings . 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