CA2235967C - Diarylethylene metallocene derivatives, their processes of preparation and pharmaceutical compositions containing said derivatives - Google Patents
Diarylethylene metallocene derivatives, their processes of preparation and pharmaceutical compositions containing said derivatives Download PDFInfo
- Publication number
- CA2235967C CA2235967C CA002235967A CA2235967A CA2235967C CA 2235967 C CA2235967 C CA 2235967C CA 002235967 A CA002235967 A CA 002235967A CA 2235967 A CA2235967 A CA 2235967A CA 2235967 C CA2235967 C CA 2235967C
- Authority
- CA
- Canada
- Prior art keywords
- group
- compound
- atom
- phenyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Compounds of general Formula (I), (see fig I) wherein R3, R4, R5 and Z are as specifically defined, are provided herein, as well as their processes of preparation; and pharmaceutical compositions containing them. Thesederivatives are suitable for the preparation of antitumoral drugs for use, in particular, in the treatment of estrogen-dependent cancers.
Description
(a) TI'JCLE OF THE INVENTION
DIARYLE;THYLENE METALLOCENE DERIVATIVES, THEIR PROCESSES OF
PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID
DERIVATIVES
(b) TECHNICAL FIELD TO WHICH THE INVENTION RELATES
The present invention relates to diarylethylene metallocene derivatives, to their processes of preparation, to pharmaceutical composition containing such derivatives, and to their use in the preparation of antitumoral drugs for use, in particular, in the treatment of estrogen-dependent breast cancers.
This application is a division of application Serial No. 2,202,169 filed October 11, 1995.
(c) B~~CKGROUND ART
Some classes of triarylethylene derivatives have representatives, e. g. , tamoxifen or nafoxidine, which combine weak estrogenic properties with marked antiestrogenic properties which are the basis of their use as oral contraceptives (Ray et al., J. Med.
Chem., 1'94, 37, 696), as inducers of ovulation, and, in particular as antitumour agents (Jordan and Murphy, Edocr. Rev.., 1990, 11, 578; Dore et al., J. Med. Chem., 1992, 35, 573; Kym et al., J. Med. Chem., 1993, 36, 3910).
This duality of weak estrogenic and pronounced antiestrogenic properties doubtless results from the presence of two distinct functional components in the structure of these, compounds. It includes, on the one hand, an entity of the traps-stilbene type which simulates the structure of the synthetic estrogen, diethylstilbestrol, and, on the other hand, an additional polar residue composed, for example, of a group of the (?~-tert-aminoalkoxy)phenyl type which interferes with the initiation of the estrogenic activity and is responsible for the antiestrogenic activity.
Tlhe hypothesis of the presence of coordinating acidic Zn++ in the region of the association site of the hormone has recently been advanced to explain this behaviour (Jaouen c;t al., Acc. Chem. Res., 1993, 26, 361).
DIARYLE;THYLENE METALLOCENE DERIVATIVES, THEIR PROCESSES OF
PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID
DERIVATIVES
(b) TECHNICAL FIELD TO WHICH THE INVENTION RELATES
The present invention relates to diarylethylene metallocene derivatives, to their processes of preparation, to pharmaceutical composition containing such derivatives, and to their use in the preparation of antitumoral drugs for use, in particular, in the treatment of estrogen-dependent breast cancers.
This application is a division of application Serial No. 2,202,169 filed October 11, 1995.
(c) B~~CKGROUND ART
Some classes of triarylethylene derivatives have representatives, e. g. , tamoxifen or nafoxidine, which combine weak estrogenic properties with marked antiestrogenic properties which are the basis of their use as oral contraceptives (Ray et al., J. Med.
Chem., 1'94, 37, 696), as inducers of ovulation, and, in particular as antitumour agents (Jordan and Murphy, Edocr. Rev.., 1990, 11, 578; Dore et al., J. Med. Chem., 1992, 35, 573; Kym et al., J. Med. Chem., 1993, 36, 3910).
This duality of weak estrogenic and pronounced antiestrogenic properties doubtless results from the presence of two distinct functional components in the structure of these, compounds. It includes, on the one hand, an entity of the traps-stilbene type which simulates the structure of the synthetic estrogen, diethylstilbestrol, and, on the other hand, an additional polar residue composed, for example, of a group of the (?~-tert-aminoalkoxy)phenyl type which interferes with the initiation of the estrogenic activity and is responsible for the antiestrogenic activity.
Tlhe hypothesis of the presence of coordinating acidic Zn++ in the region of the association site of the hormone has recently been advanced to explain this behaviour (Jaouen c;t al., Acc. Chem. Res., 1993, 26, 361).
Whatever the nature of the molecular process involved, tamoxifen is widely used as adjuvant therapy in the control of cancers of the breast responding positively to analysis of estradiol receptors. This molecule has a positive effect on the survival of the patients and is, moreover, well tolerated.
However, as the action of tamoxifen is tumoristatic rather than tumoricidal, its use in this indication generally justifies prolonged administration, during which some patients develop resistance to the treatment (Wolf and Jordan, Breast Cancer Res. Treat. , 1993, 27, 27). In extreme cases, some tumours of the breast and of the endometrium end up by growing by stimulation with tamoxifen.
For this reason, the problem is posed of developing new molecules which possess antitumour properties and which are capable of replacing the triarylethylene antiestrogens of the prior art, in particular tamoxifen, in their antitumour applications, e. g. , the treatment of estrogen-dependent cancers of the breast.
(d) DESCRIPTION OF THE INVENTION
The present invention provides a new family of compounds which are capable of acting advantageously as substitutes for the triarylethylene antiestrogens of the prior art, in particular, tamoxifen, because they exhibit an antitumour activity which is greater than that of the latter, processes for the preparation of these new compounds and pharmaceutical compositions containing such new compounds.
By one aspect the present invention provides compounds of general Formula (I):
RsReC = CR3 COCH~nZ ( wherein the -O(CH~nZ group is in the meta or para position with respect to the -CR3=CR~RS group, n represents an integer of between 2 and 10, and Z
represents a basic or polar ligand which is selected from -NR,R2 groups, wherein Rl and R2, which are identical or different, represent an unsubstituted C, to C6 alkyl group or a C, to C6 alkyl group which is substituted by at least one halogen atom, or a -~R, group, or a -SOR, group, or a ~OZRI group, wherein R, has the same meaning as above, and wherein either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C, to C3 alkyl group, or by at least one C, to C3 alkoxy group, R4 represents a hydrogen atom, or a.halogen atom, or an NOZ
group, or a chloroethyl group, or a CN group, or alternatively a Ci to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and RS represents a metallocene group, which corresponds to the general Formula (II) (II) wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, or an oxidized form thereof, or R3 represents a metallocene group, as hereinabove defined, and RS represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one of a hydrogen atom, or a halogen atom, or an NOZ group, or a chloroethyl group, or a CN group, or alternatively a C, to C3 alkyl group, in all its stereoisomeric forms and its salts.
Unexpectedly, it has been discovered that the attachment, to the same skeleton, of an antiestrogenic component and of a particularly-specified metallocene entity, results in compounds which have marked tumoristatic and tumoricidal properties which are superior to those of the antiestrogens of the prior art and, for this reason, are capable of being used as antitumour agents, in particular in the treatment of estrogen-dependant cancers of the breast.
In the preceding and the following, the expression "C1 to C6 alkyl" denotes any linear or branched alkyl group having no more than 6 carbon atoms, e.g., the methyl, ethyl, propyl, butyl, isopropyl or alternatively isobutyl radicals.
Similarly, the expression "C1 to C3 alkyl" denotes any linear or branched alkyl group having no more than 3 carbon atoms.
The present application is targeted at denoting, by "C, to C3 alkoxy", any alkoxy group having no more than 3 carbon atoms, e.g., a methoxy, ethoxy, propoxy or isopropoxy group.
The expression "heterocyclic group containing a nitrogen atom" denotes a nitrogenous heterocycle comprising no more than 6 atoms in the ring, e. g. , an N-piperidino, an N-morpholino or an N-pyrrolidino group.
The expression "halogen" denotes chlorine, fluorine, bromine or iodine.
By one specific variant of this broad compound aspect of this invention, the compound is one which corresponds to the specific Formula (I-a) C = CR3 O(CH~ZZ
M (I-a) wherein the -O(CH~ZZ group is the para position with respect to the -CR3=CR4R5 group, and Z represents an -NR,R2 group, wherein R, and R2, which are identical or different, represent a methyl group, or an ethyl group, or alternatively Z
represents an N-pyrrolidino group, R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by a hydroxyl group or by a methoxy group, R4 represents a hydrogen atom, or a halogen atom, or an N02 group, or a chloroethyl group, or a CN
group, or alternatively, an ethyl group, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of such selected metal.
By a second variant of this compound aspect of the present invention, R, and RZ
represent a methyl group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl group and R4 represents an ethyl group, the compound thereby corresponding to the specific Formula (I-a) By a third and specific variant of this compound aspect of the present invention, the compound is 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxy-phenyl)-2-ferrocenyl-1-butene.
These compounds can form isomers so that, by a fourth and specific variant of this compound aspect of the present invention, the compound is the "traps"
isomer of 1 [4-(2-dimethylaminoethoxy)phenyl]-(4-hydroxyphenyl)-2-ferrocenyl-1-butene.
By a fifth variant of the compound aspect of the present invention, R, and R2 each represent a methyl group, R3 represents a phenyl group, and R4 represents an ethyl group.
By a sixth and specific variant of the compound aspect of the present invention, the compound is 1-[4-(2-dimethylaminoethoxy)phenyl)-1-phenyl-2-ferrocenyl-1-butene.
By a seventh variant of this compound aspect of the present invention, the -O(CH~"Z group is in the para position with respect to the -CR3=CR~RS group, n is equal to 2 and Z represents an N-pyrrolidino group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl, or by a C, to C3 alkoxy group, and R4 represents a C2 alkyl group, the end carbon of which is bonded to the carbon which is situated in the 2 position of the phenyl group of R3, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of the metal.
By a second aspect of this invention, a process is provided for preparing the above-described compounds, the process comprising a) reacting a compound of general Formula (IV):
However, as the action of tamoxifen is tumoristatic rather than tumoricidal, its use in this indication generally justifies prolonged administration, during which some patients develop resistance to the treatment (Wolf and Jordan, Breast Cancer Res. Treat. , 1993, 27, 27). In extreme cases, some tumours of the breast and of the endometrium end up by growing by stimulation with tamoxifen.
For this reason, the problem is posed of developing new molecules which possess antitumour properties and which are capable of replacing the triarylethylene antiestrogens of the prior art, in particular tamoxifen, in their antitumour applications, e. g. , the treatment of estrogen-dependent cancers of the breast.
(d) DESCRIPTION OF THE INVENTION
The present invention provides a new family of compounds which are capable of acting advantageously as substitutes for the triarylethylene antiestrogens of the prior art, in particular, tamoxifen, because they exhibit an antitumour activity which is greater than that of the latter, processes for the preparation of these new compounds and pharmaceutical compositions containing such new compounds.
By one aspect the present invention provides compounds of general Formula (I):
RsReC = CR3 COCH~nZ ( wherein the -O(CH~nZ group is in the meta or para position with respect to the -CR3=CR~RS group, n represents an integer of between 2 and 10, and Z
represents a basic or polar ligand which is selected from -NR,R2 groups, wherein Rl and R2, which are identical or different, represent an unsubstituted C, to C6 alkyl group or a C, to C6 alkyl group which is substituted by at least one halogen atom, or a -~R, group, or a -SOR, group, or a ~OZRI group, wherein R, has the same meaning as above, and wherein either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C, to C3 alkyl group, or by at least one C, to C3 alkoxy group, R4 represents a hydrogen atom, or a.halogen atom, or an NOZ
group, or a chloroethyl group, or a CN group, or alternatively a Ci to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and RS represents a metallocene group, which corresponds to the general Formula (II) (II) wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, or an oxidized form thereof, or R3 represents a metallocene group, as hereinabove defined, and RS represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one of a hydrogen atom, or a halogen atom, or an NOZ group, or a chloroethyl group, or a CN group, or alternatively a C, to C3 alkyl group, in all its stereoisomeric forms and its salts.
Unexpectedly, it has been discovered that the attachment, to the same skeleton, of an antiestrogenic component and of a particularly-specified metallocene entity, results in compounds which have marked tumoristatic and tumoricidal properties which are superior to those of the antiestrogens of the prior art and, for this reason, are capable of being used as antitumour agents, in particular in the treatment of estrogen-dependant cancers of the breast.
In the preceding and the following, the expression "C1 to C6 alkyl" denotes any linear or branched alkyl group having no more than 6 carbon atoms, e.g., the methyl, ethyl, propyl, butyl, isopropyl or alternatively isobutyl radicals.
Similarly, the expression "C1 to C3 alkyl" denotes any linear or branched alkyl group having no more than 3 carbon atoms.
The present application is targeted at denoting, by "C, to C3 alkoxy", any alkoxy group having no more than 3 carbon atoms, e.g., a methoxy, ethoxy, propoxy or isopropoxy group.
The expression "heterocyclic group containing a nitrogen atom" denotes a nitrogenous heterocycle comprising no more than 6 atoms in the ring, e. g. , an N-piperidino, an N-morpholino or an N-pyrrolidino group.
The expression "halogen" denotes chlorine, fluorine, bromine or iodine.
By one specific variant of this broad compound aspect of this invention, the compound is one which corresponds to the specific Formula (I-a) C = CR3 O(CH~ZZ
M (I-a) wherein the -O(CH~ZZ group is the para position with respect to the -CR3=CR4R5 group, and Z represents an -NR,R2 group, wherein R, and R2, which are identical or different, represent a methyl group, or an ethyl group, or alternatively Z
represents an N-pyrrolidino group, R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by a hydroxyl group or by a methoxy group, R4 represents a hydrogen atom, or a halogen atom, or an N02 group, or a chloroethyl group, or a CN
group, or alternatively, an ethyl group, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of such selected metal.
By a second variant of this compound aspect of the present invention, R, and RZ
represent a methyl group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl group and R4 represents an ethyl group, the compound thereby corresponding to the specific Formula (I-a) By a third and specific variant of this compound aspect of the present invention, the compound is 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxy-phenyl)-2-ferrocenyl-1-butene.
These compounds can form isomers so that, by a fourth and specific variant of this compound aspect of the present invention, the compound is the "traps"
isomer of 1 [4-(2-dimethylaminoethoxy)phenyl]-(4-hydroxyphenyl)-2-ferrocenyl-1-butene.
By a fifth variant of the compound aspect of the present invention, R, and R2 each represent a methyl group, R3 represents a phenyl group, and R4 represents an ethyl group.
By a sixth and specific variant of the compound aspect of the present invention, the compound is 1-[4-(2-dimethylaminoethoxy)phenyl)-1-phenyl-2-ferrocenyl-1-butene.
By a seventh variant of this compound aspect of the present invention, the -O(CH~"Z group is in the para position with respect to the -CR3=CR~RS group, n is equal to 2 and Z represents an N-pyrrolidino group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl, or by a C, to C3 alkoxy group, and R4 represents a C2 alkyl group, the end carbon of which is bonded to the carbon which is situated in the 2 position of the phenyl group of R3, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of the metal.
By a second aspect of this invention, a process is provided for preparing the above-described compounds, the process comprising a) reacting a compound of general Formula (IV):
RsReC = CR3 O-(CHz)"Z (IV) wherein the -O(CHZ)"Z group is in the meta or para position with respect to the -CR3=CR4R5 group, n represents an integer of between 2 and 10, and Z
represents a basic or polar ligand which is selected from -NR,R2 groups, wherein R, and R2, which are identical or different, represent an unsubstituted C, to C6 alkyl group or a C1 to C6 alkyl group which is substituted by at least one halogen atom, or at least one heterocyclic group containing a nitrogen atom, or at least one -ORl group, or at least one -SRl group, or at least one -FOR, group, or at least one -~02R, group, wherein R, has the same meaning as above, and wherein either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group or by at least one C1 to C3 alkyl group, or by at least one C, to C3 alkoxy group, R4 represents a hydrogen atom, or a halogen atom, or an N02 group, or a chloroethyl group, or a CN group, or alternatively a CI to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and RS
represents a bromine atom, or R3 represents a bromine atom, R4 represents a hydrogen atom, or a halogen atom, or an N02 group, or a chloroethyl group, or a CN group, or alternatively a C, to C3 alkyl group, and RS represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C, to C3 alkyl group, or by at least one C, to C3 alkoxy group, with a cyclopentadienyl metal salt, in order to substitute the bromine atom by a cyclopentadiene group, b) reacting the compound obtained in Stage a) with a strong base, in order to form a cyclopentadienyl anion, and c) reacting the compound obtained in Stage b) with an organometallic compound of the Formula:
M
(CO)2-X
wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, and X represents a halogen atom which is selected from the group consisting of chlorine, bromine or iodine.
The compounds of general Formula (IV) can be prepared according to the processes which have been provided in the prior art for the synthesis of triarylethylene antiestrogens (Cur. Med. Chem., 1994, 1, 61-104).
A cyclopentadienyl metal salt which is suitable for the implementation of Stage a) of this process is represented by sodium cyclopentadienylide.
represents a basic or polar ligand which is selected from -NR,R2 groups, wherein R, and R2, which are identical or different, represent an unsubstituted C, to C6 alkyl group or a C1 to C6 alkyl group which is substituted by at least one halogen atom, or at least one heterocyclic group containing a nitrogen atom, or at least one -ORl group, or at least one -SRl group, or at least one -FOR, group, or at least one -~02R, group, wherein R, has the same meaning as above, and wherein either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group or by at least one C1 to C3 alkyl group, or by at least one C, to C3 alkoxy group, R4 represents a hydrogen atom, or a halogen atom, or an N02 group, or a chloroethyl group, or a CN group, or alternatively a CI to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and RS
represents a bromine atom, or R3 represents a bromine atom, R4 represents a hydrogen atom, or a halogen atom, or an N02 group, or a chloroethyl group, or a CN group, or alternatively a C, to C3 alkyl group, and RS represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C, to C3 alkyl group, or by at least one C, to C3 alkoxy group, with a cyclopentadienyl metal salt, in order to substitute the bromine atom by a cyclopentadiene group, b) reacting the compound obtained in Stage a) with a strong base, in order to form a cyclopentadienyl anion, and c) reacting the compound obtained in Stage b) with an organometallic compound of the Formula:
M
(CO)2-X
wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, and X represents a halogen atom which is selected from the group consisting of chlorine, bromine or iodine.
The compounds of general Formula (IV) can be prepared according to the processes which have been provided in the prior art for the synthesis of triarylethylene antiestrogens (Cur. Med. Chem., 1994, 1, 61-104).
A cyclopentadienyl metal salt which is suitable for the implementation of Stage a) of this process is represented by sodium cyclopentadienylide.
The strong base which is useful for the implementation of Stage b) can be, e.g., NaH or NaNH2.
By one variant of this second process aspect of the present invention, the process comprises a) subjecting a metallocene ester of Formula (V):
By one variant of this second process aspect of the present invention, the process comprises a) subjecting a metallocene ester of Formula (V):
10 CH,CH3 -M
(V) wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, to an addition reaction with an organolithium compound CH3-4--C6H4 Li or with an organomagnesium compound CH3-~4-C6H4 MgX, wherein X represents a chlorine atom, a bromine atom or an iodine atom, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of the alcohol, b) subjecting the compound obtained in Stage a) to a demethylation reaction, and c) subjecting the compound obtained in Stage b) to an alkylation reaction with sodium ethoxide and the hydrochloride of 2-dimethylaminoethyl chloride.
The dehydration of the intermediate alcohol can advantageously be carried out by the action of a strong acid, e.g., hydrochloric acid.
The demethylation reaction can advantageous be carried out by the action of boron tribromide in the presence of an appropriate solvent, e.g., dichloromethane.
5 By a second variant of this second process aspect of the present invention, the process includes the preliminary step of the preparation of the metallocene ester of Formula (V) by esterification of the corresponding metallocenylacetic acid, followed by an alkylation reaction of the carbon in the position a to the metallocenyl ring of the ester.
The metallocenylacetic acid can be esterified by means of a strong base, e.g., 10 potassium tert-butoxide (t-BuOK).
A suitable alkylating reagent is represented by iodoethane. This alkylation is advantageously carried out in the presence of a strong base, e.g., t-BuOK or sodium or potassium hexamethyldisilazanide, and of an appropriate solvent, e.g., dimethyl sulfoxide (DMSO).
The metallocenylacetic acid can be prepared according to the method described in the literature (Lednicer et al., J. Org. Chem., 1958, 23, 653), which comprises the reaction of a metallocenylmethyltrimethylammonium iodide with potassium cyanide, in order to obtain the corresponding metallocenylacetonitrile, and then the hydrolysis of the latter.
(V) wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, to an addition reaction with an organolithium compound CH3-4--C6H4 Li or with an organomagnesium compound CH3-~4-C6H4 MgX, wherein X represents a chlorine atom, a bromine atom or an iodine atom, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of the alcohol, b) subjecting the compound obtained in Stage a) to a demethylation reaction, and c) subjecting the compound obtained in Stage b) to an alkylation reaction with sodium ethoxide and the hydrochloride of 2-dimethylaminoethyl chloride.
The dehydration of the intermediate alcohol can advantageously be carried out by the action of a strong acid, e.g., hydrochloric acid.
The demethylation reaction can advantageous be carried out by the action of boron tribromide in the presence of an appropriate solvent, e.g., dichloromethane.
5 By a second variant of this second process aspect of the present invention, the process includes the preliminary step of the preparation of the metallocene ester of Formula (V) by esterification of the corresponding metallocenylacetic acid, followed by an alkylation reaction of the carbon in the position a to the metallocenyl ring of the ester.
The metallocenylacetic acid can be esterified by means of a strong base, e.g., 10 potassium tert-butoxide (t-BuOK).
A suitable alkylating reagent is represented by iodoethane. This alkylation is advantageously carried out in the presence of a strong base, e.g., t-BuOK or sodium or potassium hexamethyldisilazanide, and of an appropriate solvent, e.g., dimethyl sulfoxide (DMSO).
The metallocenylacetic acid can be prepared according to the method described in the literature (Lednicer et al., J. Org. Chem., 1958, 23, 653), which comprises the reaction of a metallocenylmethyltrimethylammonium iodide with potassium cyanide, in order to obtain the corresponding metallocenylacetonitrile, and then the hydrolysis of the latter.
Insofar as the preparation of the metallocene derivative according to the process of this aspect of the present invention always results in the production of the two "cis"
and "traps" isomers of the derivative, and as generally only one of the two isomers, namely the "traps" isomers of the derivative, and as generally only one of the two isomers, namely the "traps" isomer, exhibits pronounced antiestrogenic properties, it is advantageous to proceed to a separation of the two isomers obtained on conclusion of above-mentioned Stage c). Thus, by a third variant of the second process aspect of the present invention includes the additional step of the separation of the "cis"
and "traps"
isomers of the compound so-obtained.
The separation can advantageously be carried out by fractional crystallization.
It is, however, possible to use other techniques of the prior art, e. g. , thin-layer chromatography using an appropriate eluent.
By a fourth variant of this second process aspect of this invention, the process comprises a) reacting a metallocenic acid chloride of Formula (VI):
~HzCHs CIHCOCI
M
(VI) wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, with diphenylzinc, in order to substitute the chlorine atom by a phenyl group; and b) subjecting the compound which is obtained in Stage a) to an addition reaction with an organolithium compound (CH3)2-N-(CH~2-O-C6H4 Li, or with an organomagnesium compound (CH3)2-N-(CH~2-O-C6H4 MgX, wherein X represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of the alcohol.
A mixture of the two "cis" and "traps" isomers of the compound is thus obtained.
The preparation of this compound according to the process of this aspect of the present invention always results in the production of the two "cis" and "traps"
isomers of the compound, so that it comprises in addition a stage of separation of these "cis" and "traps" isomers, which separation can be carried out, for example, by fractional crystallization. Accordingly, by a fifth variant of this second process aspect of this invention, the process includes the additional step of the separation of the "cis" and "traps" isomers of the compound so-obtained.
The metallocenic acid chloride can be obtained by the reaction of phosphorus trichloride or pentachloride or thionyl chloride or alternatively of triphosgene with the corresponding 2-metallocenylbutanoic acid.
The dehydration of the intermediate alcohol can be carried out by the action of a strong acid, hydrochloric acid.
By a sixth variant of this second process aspect of this invention, the process comprises a) reacting a tetralone of Formula (VII):
and "traps" isomers of the derivative, and as generally only one of the two isomers, namely the "traps" isomers of the derivative, and as generally only one of the two isomers, namely the "traps" isomer, exhibits pronounced antiestrogenic properties, it is advantageous to proceed to a separation of the two isomers obtained on conclusion of above-mentioned Stage c). Thus, by a third variant of the second process aspect of the present invention includes the additional step of the separation of the "cis"
and "traps"
isomers of the compound so-obtained.
The separation can advantageously be carried out by fractional crystallization.
It is, however, possible to use other techniques of the prior art, e. g. , thin-layer chromatography using an appropriate eluent.
By a fourth variant of this second process aspect of this invention, the process comprises a) reacting a metallocenic acid chloride of Formula (VI):
~HzCHs CIHCOCI
M
(VI) wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, with diphenylzinc, in order to substitute the chlorine atom by a phenyl group; and b) subjecting the compound which is obtained in Stage a) to an addition reaction with an organolithium compound (CH3)2-N-(CH~2-O-C6H4 Li, or with an organomagnesium compound (CH3)2-N-(CH~2-O-C6H4 MgX, wherein X represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of the alcohol.
A mixture of the two "cis" and "traps" isomers of the compound is thus obtained.
The preparation of this compound according to the process of this aspect of the present invention always results in the production of the two "cis" and "traps"
isomers of the compound, so that it comprises in addition a stage of separation of these "cis" and "traps" isomers, which separation can be carried out, for example, by fractional crystallization. Accordingly, by a fifth variant of this second process aspect of this invention, the process includes the additional step of the separation of the "cis" and "traps" isomers of the compound so-obtained.
The metallocenic acid chloride can be obtained by the reaction of phosphorus trichloride or pentachloride or thionyl chloride or alternatively of triphosgene with the corresponding 2-metallocenylbutanoic acid.
The dehydration of the intermediate alcohol can be carried out by the action of a strong acid, hydrochloric acid.
By a sixth variant of this second process aspect of this invention, the process comprises a) reacting a tetralone of Formula (VII):
~VII>
__ wherein R6 represents a hydrogen atom or a C, to C3 alkyl group, with an organolithium compound N-yH~z'--O--C~Ha 1-i, or with an organomagnesium compound N-(CH~2-O--C6H4 MgX, wherein X represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of the alcohol, b) subjecting the compound which is obtained in Stage a) to a bromination reaction, in order to obtain the compound of Formula (VIII):
v o(CH~~v and c) subjecting the compound of Formula (VIII) thus obtained to a coupling reaction with an organometallic compound of the Formula:
M
(CSH4)y wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, and Y represents a lithium atom, a copper atom, an SnBu3 group or an HgCI group.
The bromination reaction to which the compound of Formula (VIII) is subjected 5 can be carried out with hydrobromic acid in the presence of an appropriate solvent, e.g., pyridine.
The products of general Formula (I) and their addition salts with acids which are acceptable from the pharmacological viewpoint according to aspects of the present invention, can be administered to man as medicaments, alone or in the form of 10 pharmaceutical compositions which make possible_enteral or parenteral application and which contain, as an active constituent, an effective dose of at least one product of Formula (I) or an acid addition salt of such a compound with, in addition, inoffensive excipients and additives taken from those commonly used in pharmaceuticals.
Thus, by a seventh aspect of this invention, a medicament is provided which is 15 either at least one of the compound of Formula (I) as described above, and one of its salts, or a pharmaceutical composition, comprising at least one of the compound of Formula (I) or one of its salts, as described above as active constituent in an effective dose in combination with a pharmacologically-acceptable vehicle.
The products of general Formula (I) and their salts of aspects of this invention, find, due to their tumoristatic and tumoricidal properties, application in the preparation of medicaments with an antitumour purpose, in particular in the treatment of estrogen-dependent cancers of the breast. Thus, by an eighth aspect of this invention, the use is provided of the compound of general Formula (I) or of one of its salts as described above for the production of an antitumour medicament.
__ wherein R6 represents a hydrogen atom or a C, to C3 alkyl group, with an organolithium compound N-yH~z'--O--C~Ha 1-i, or with an organomagnesium compound N-(CH~2-O--C6H4 MgX, wherein X represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of the alcohol, b) subjecting the compound which is obtained in Stage a) to a bromination reaction, in order to obtain the compound of Formula (VIII):
v o(CH~~v and c) subjecting the compound of Formula (VIII) thus obtained to a coupling reaction with an organometallic compound of the Formula:
M
(CSH4)y wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, and Y represents a lithium atom, a copper atom, an SnBu3 group or an HgCI group.
The bromination reaction to which the compound of Formula (VIII) is subjected 5 can be carried out with hydrobromic acid in the presence of an appropriate solvent, e.g., pyridine.
The products of general Formula (I) and their addition salts with acids which are acceptable from the pharmacological viewpoint according to aspects of the present invention, can be administered to man as medicaments, alone or in the form of 10 pharmaceutical compositions which make possible_enteral or parenteral application and which contain, as an active constituent, an effective dose of at least one product of Formula (I) or an acid addition salt of such a compound with, in addition, inoffensive excipients and additives taken from those commonly used in pharmaceuticals.
Thus, by a seventh aspect of this invention, a medicament is provided which is 15 either at least one of the compound of Formula (I) as described above, and one of its salts, or a pharmaceutical composition, comprising at least one of the compound of Formula (I) or one of its salts, as described above as active constituent in an effective dose in combination with a pharmacologically-acceptable vehicle.
The products of general Formula (I) and their salts of aspects of this invention, find, due to their tumoristatic and tumoricidal properties, application in the preparation of medicaments with an antitumour purpose, in particular in the treatment of estrogen-dependent cancers of the breast. Thus, by an eighth aspect of this invention, the use is provided of the compound of general Formula (I) or of one of its salts as described above for the production of an antitumour medicament.
(e) DESCRIPTION OF THE FIGURES
In the accompanying drawings, Figures lA, 1B and 2 show the results of the cytotoxicity tests carried out respectively with the two isomers of a metallocene derivative in accordance with aspects of the invention and with tamoxifen.
(f) AT LEAST ONE MODE FOR CARRYING OUT THE INVENTION
It should be clearly understood that these examples are given by way of illustration of aspects of the invention.
EXAMPLE 1: Preparation of the "trans" and "cis" isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butene 1:1: Preparation of ferrocenylacetonitrile 8.00 g (20.8 mmol) of ferrocenylmethyltrimethylammonium iodide (Strem) and 8 g of KCN (123 mmol) are dissolved in 80 ml of water. The mixture is placed in a round-bottomed flask surmounted by a reflux condenser. The mixture is heated at reflux for 2 hours and is then allowed to cool to room temperature. The product is extracted with 3 times 40 ml of ethyl ether. The organic phase is washed first with 2 times 30 ml of water and then dried over magnesium sulphate. After filtration and evaporation, 4.1 g of ferrocenylacetonitrile are collected.
Chemical formula: C,ZH"NFe Mass: 225 Yield: 87.7 1.2: Preparation of ferrocenylacetic acid 4.10 g (18.2 mmol) of ferrocenylacetonitrile are dissolved in 80 ml of ethanol.
10.08 g of KOH (190 mmol) are dissolved in 80 ml of ethanol. 10.08 g of KOH
(180 mmol) are dissolved in 80 ml of water. The potassium hydroxide solution is poured into the first solution and the mixture is brought to reflux for 4 hours. The reaction mixture is concentrated in order to remove most of the ethanol. The product is extracted with 3 times 30 ml of ether. The aqueous phase is acidified with hydrochloric acid to a pH
of 1 and is again extracted with 4 times 50 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and then evaporated. 4.20 g of ferrocenylacetic acid are obtained in the form of a yellow solid.
Chemical formula : C1zH120zc a Mass: 244 Yield: 94.5 1H NMR (200 MHz, CDC13): 8 4.23 (m, 2H, substituted Cp), 4.15 (s, 7H, Cp and substituted Cp), 3.42 (s, 2H, CHz).
1.3: Preparation of ethyl ferrocenylacetate 2.00 g (8.2 mmol) of ferrocenylacetic acid are dissolved in 50 m1 of ethanol. 0.5 ml of concentrated sulfuric acid is added. The mixture is brought to reflux for 1 hour. After cooling, the reaction mixture is poured into 100 ml of ice-cold water. The product is extracted with 3 times 40 ml of ether. The ethereal phase is first washed with water (2 times 40 ml) and then dried over magnesium sulfate, filtered and evaporated. 2.22 g of ethyl ferrocenylacetate are obtained. The yield of the reaction is 100.
Chemical formula: Cl4HisOzFe Mass: 272 1H NMR (200 MHz, CDC13): 8 4.23 (m, 2H, substituted Cp), 4.18 (m, 2H, 0-CHz), 4.14 (s, 5H, Cp), 4.13 (m, 2H, substituted Cp), 3.34 (s, 2H, Cp-CHz), 1.31 (t, 3H, J =
7.12 Hz, Me).
1.4: Preparation of ethyl 2-ethyl-2-ferrocenylacetate 2.22 g (8.2 mmo1) of ethyl ferrocenylacetate are dissolved in 25 ml of anhydrous DMSO under an argon atmosphere. 1.01 g (9 mmol) of t-BuOK are added. After stirring for S minutes, 1.5 g (9.6 mmol) of iodoethane are rapidly added. Stirring is continued for 2 minutes and then the reaction mixture is poured into 100 ml of ice-cold water. The product is extracted with 3 times 50 ml of ether. The ethereal phase is washed twice with 50 ml of water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GFzs4 (Merck 7730) silica gel plates with a thickness of 1 mm with a 1/9 ether/pentane mixture as eluent.
1.16 g of ethyl 2-ethyl-2-ferrocenylacetate are obtained (R~ = 0.6) with a yield of 47$.
Chemical formula : C, SHzoOzF a Mass: 300 iH NMR (200 MHz, CDC13): S 4.23 (m, 2H, substituted Cp), 4.16 (m, 2H, 0-CH=), 4.13 (s, SH, Cp), 4.12 (m, 2H, substituted Cp), 3.19 (m, 1H, Fc-CH-), 1.77 (m, 2H, Fc-CH-CHI ) , 1 . 3 S (T, 3H , J - 7 . 14 Hz , 0-CHZ-CH3 ) , 0 . 92 ( t, 3H, J = 7.38 Hz, CH-CHz-CH3) .
1.5: Preparation of 1,1-bis(4-methoxyphenyl)-2-ferrocenyl-1-butane 1.20 g (5.5 mmol) of 4-iodoanisole are dissolved in 20 ml of anhydrous ether under an argon atmosphere. The solution is cooled to 0°C and then 2.9 ml (4.6 mmo1) of a 1.6M n-butyllithium solution are added dropwise. After complete addition, the mixture is maintained at 0°C for 15 minutes. A solution of ethyl 2-ethyl-2-ferrocenylacetate (0.69 g, 2.3 mmol) dissolved in 10 ml of anhydrous ether is placed in the dropping funnel. The latter solution is added dropwise to the first solution, the temperature being maintained at 0°C. Stirring is maintained for 30 minutes at 0°C
and 2 hours at room temperature. A 1N hydrochloric acid solution is then added to a pH of 1 and the reaction mixture is heated at reflux for 4 hours. After cooling, the product is extracted with ether. The ethereal phase is first washed with water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GF254 silica gel plates with a 1/9 ether/pentane mixture as eluent.
0.65 g of the desired compound is obtained (RE - 0.45) with a yield of 62.5.
3 5 Chemical formula : CZBHZe02Fe Mass: 452 1H NMR (200 MHz, CDC13) : 8 7.12 and 6.16 (dd, 4H, J = 8.4 Hz, C6H4), 6.98 and 6.87 (dd, 4H, J - 8.4 Hz, C6H4), 4.14 (s, 5H, Cp), 4.10 (m, 2H, substituted Cp), 3.95 (m, 2H, substituted Cp), 3.32 and 3.78 (s, s, 3H, 3H, 0-Me), 2.56 (q, 2H, J - 7.4 Hz, -CHz-CH3), 1.02 ( t , 3 H , J = 7 . 3 Hz , -CH=-CH3 ) .
1.6 . Preparation of l,l-bis(4-hydroxyphenyl)-2-ferrocenyl-1-butene 0.55 g (1.28 mmol) of 1,1-bis(4-methoxyphenyl)-2-ferrocenyl-1-butene is dissolved in 5 ml of dichloromethane under an argon atmosphere. The solution is cooled to -78°C and then 0.3 ml (2.84 mmol) of BBr3 is added. After complete addition, the cold bath is removed and stirring is maintained for 30 minutes. The reaction mixture is then poured into ice-cold water.
After stirring for 10 minutes, NaCl is added to saturation and the product is extracted with dichloromethane (4 times 40 ml). The organic phase is first washed with water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GF2;~ silica gel plates with a 3/2 ether/pentane mixture as eluent.
0.43 g of the desired compound is obtained (RF - 0.4;
yield = 79~).
Chemical formula: Cz6H~aO2Fe Mass: 424 1H NMR (200 MHz, CDC13) : b 7.07 and 6.68 (d, d, 4H, J = 8.6 Hz, C6H4) , 6.92 and 6.80 (d, d, 4H, J = 8.5 Hz, C6H4), 4.88 and 4.42 (s, s, H, H, 2 OH), 4.11 (s, 5H, Cp), 4.08 (m, 2H, substituted Cp), 3.91 (m, 2H, substituted Cp), 2.58 (q, 2H, J = 7.5 Hz, -CHZ-CH3), 1.02 (t, 3H, J = 7.5 Hz, -CHZ-CH3) .
1.7: Production of the "trans" and °cis" isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane A sodium ethoxide solution is first prepared by reacting 0.120 g (5.2 mmol) of sodium with 20 ml of ethanol. 0.450 g (1.06 mmol) of 1,1-bis(4-hydroxyphenyl)-2-ferrocenyl-1-butane, dissolved in 10 ml of ethanol, is then added to this solution. After stirring for 1 hour at 80°C, 0.302 g (2.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride is added and the mi:cture is heated at reLlu:c ~or 3 hours. The solution is then allowed to cool to room temperature.
.-:rdrolysis is carried out with 100 m? of water and the product is e:<tracted with ether (4 times 50 ml) . The S orga:~ic phase is first washed wits. water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60Gr'~;;
silica gel places wi tz a 1/9 (C~ ;) ~N/ch'_orofor:,l mi:cture as eluent.
1.0 0.280 g of the mixture of the "trays" isomer and of the "cis" isomer of 1-[4-(2-dimethyla~-ninoethoxy)phenyl]-1-(4-hydro:cyphenyl)-2-ferrocenyl-1-butane is first obtained ('field = 53~).
The second, more polar, fraction corresponds to 15 1,1-bis[4-(2-dimethylaminoethoxy)phenyl]-2-ferrocenyl-1-butane (0.050 g; Yield = 9.5~).
1.8: Separation of the "traps" and "cis" isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane 20 The mixture of the two isomers obtained above is dissolved in an ether/hexane (5/1) mixture and the solution obtained is left in a refrigerator overnight.
As the solubility in ether of the "cis" isomer is lower than that of the "traps" isomer, the "cis"
2.'~ isomer crystallizes first after gentle evaporation of the solvent. The crystals of the "cis" isomer are isolated and the mother liquors are recooled in the freezer compartment (-15°C) of the refrigerator for one day. The "traps" isomer then crystallizes in its turn in the form of fine needles.
EXAMPLE 2: Characterization of the "traps" and "cis"
isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane 2.1: Chemical formula and molar mass 3 5 Chemical formula : C3oH330zNFe Molar mass: 495.4 2.2: 1H NI~t spectrometric data The iH NMR spectra of the two "traps" and "cis"
isomers were recorded on a spectrometer known by the Trade-mark BRUCKERTM
In the accompanying drawings, Figures lA, 1B and 2 show the results of the cytotoxicity tests carried out respectively with the two isomers of a metallocene derivative in accordance with aspects of the invention and with tamoxifen.
(f) AT LEAST ONE MODE FOR CARRYING OUT THE INVENTION
It should be clearly understood that these examples are given by way of illustration of aspects of the invention.
EXAMPLE 1: Preparation of the "trans" and "cis" isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butene 1:1: Preparation of ferrocenylacetonitrile 8.00 g (20.8 mmol) of ferrocenylmethyltrimethylammonium iodide (Strem) and 8 g of KCN (123 mmol) are dissolved in 80 ml of water. The mixture is placed in a round-bottomed flask surmounted by a reflux condenser. The mixture is heated at reflux for 2 hours and is then allowed to cool to room temperature. The product is extracted with 3 times 40 ml of ethyl ether. The organic phase is washed first with 2 times 30 ml of water and then dried over magnesium sulphate. After filtration and evaporation, 4.1 g of ferrocenylacetonitrile are collected.
Chemical formula: C,ZH"NFe Mass: 225 Yield: 87.7 1.2: Preparation of ferrocenylacetic acid 4.10 g (18.2 mmol) of ferrocenylacetonitrile are dissolved in 80 ml of ethanol.
10.08 g of KOH (190 mmol) are dissolved in 80 ml of ethanol. 10.08 g of KOH
(180 mmol) are dissolved in 80 ml of water. The potassium hydroxide solution is poured into the first solution and the mixture is brought to reflux for 4 hours. The reaction mixture is concentrated in order to remove most of the ethanol. The product is extracted with 3 times 30 ml of ether. The aqueous phase is acidified with hydrochloric acid to a pH
of 1 and is again extracted with 4 times 50 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and then evaporated. 4.20 g of ferrocenylacetic acid are obtained in the form of a yellow solid.
Chemical formula : C1zH120zc a Mass: 244 Yield: 94.5 1H NMR (200 MHz, CDC13): 8 4.23 (m, 2H, substituted Cp), 4.15 (s, 7H, Cp and substituted Cp), 3.42 (s, 2H, CHz).
1.3: Preparation of ethyl ferrocenylacetate 2.00 g (8.2 mmol) of ferrocenylacetic acid are dissolved in 50 m1 of ethanol. 0.5 ml of concentrated sulfuric acid is added. The mixture is brought to reflux for 1 hour. After cooling, the reaction mixture is poured into 100 ml of ice-cold water. The product is extracted with 3 times 40 ml of ether. The ethereal phase is first washed with water (2 times 40 ml) and then dried over magnesium sulfate, filtered and evaporated. 2.22 g of ethyl ferrocenylacetate are obtained. The yield of the reaction is 100.
Chemical formula: Cl4HisOzFe Mass: 272 1H NMR (200 MHz, CDC13): 8 4.23 (m, 2H, substituted Cp), 4.18 (m, 2H, 0-CHz), 4.14 (s, 5H, Cp), 4.13 (m, 2H, substituted Cp), 3.34 (s, 2H, Cp-CHz), 1.31 (t, 3H, J =
7.12 Hz, Me).
1.4: Preparation of ethyl 2-ethyl-2-ferrocenylacetate 2.22 g (8.2 mmo1) of ethyl ferrocenylacetate are dissolved in 25 ml of anhydrous DMSO under an argon atmosphere. 1.01 g (9 mmol) of t-BuOK are added. After stirring for S minutes, 1.5 g (9.6 mmol) of iodoethane are rapidly added. Stirring is continued for 2 minutes and then the reaction mixture is poured into 100 ml of ice-cold water. The product is extracted with 3 times 50 ml of ether. The ethereal phase is washed twice with 50 ml of water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GFzs4 (Merck 7730) silica gel plates with a thickness of 1 mm with a 1/9 ether/pentane mixture as eluent.
1.16 g of ethyl 2-ethyl-2-ferrocenylacetate are obtained (R~ = 0.6) with a yield of 47$.
Chemical formula : C, SHzoOzF a Mass: 300 iH NMR (200 MHz, CDC13): S 4.23 (m, 2H, substituted Cp), 4.16 (m, 2H, 0-CH=), 4.13 (s, SH, Cp), 4.12 (m, 2H, substituted Cp), 3.19 (m, 1H, Fc-CH-), 1.77 (m, 2H, Fc-CH-CHI ) , 1 . 3 S (T, 3H , J - 7 . 14 Hz , 0-CHZ-CH3 ) , 0 . 92 ( t, 3H, J = 7.38 Hz, CH-CHz-CH3) .
1.5: Preparation of 1,1-bis(4-methoxyphenyl)-2-ferrocenyl-1-butane 1.20 g (5.5 mmol) of 4-iodoanisole are dissolved in 20 ml of anhydrous ether under an argon atmosphere. The solution is cooled to 0°C and then 2.9 ml (4.6 mmo1) of a 1.6M n-butyllithium solution are added dropwise. After complete addition, the mixture is maintained at 0°C for 15 minutes. A solution of ethyl 2-ethyl-2-ferrocenylacetate (0.69 g, 2.3 mmol) dissolved in 10 ml of anhydrous ether is placed in the dropping funnel. The latter solution is added dropwise to the first solution, the temperature being maintained at 0°C. Stirring is maintained for 30 minutes at 0°C
and 2 hours at room temperature. A 1N hydrochloric acid solution is then added to a pH of 1 and the reaction mixture is heated at reflux for 4 hours. After cooling, the product is extracted with ether. The ethereal phase is first washed with water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GF254 silica gel plates with a 1/9 ether/pentane mixture as eluent.
0.65 g of the desired compound is obtained (RE - 0.45) with a yield of 62.5.
3 5 Chemical formula : CZBHZe02Fe Mass: 452 1H NMR (200 MHz, CDC13) : 8 7.12 and 6.16 (dd, 4H, J = 8.4 Hz, C6H4), 6.98 and 6.87 (dd, 4H, J - 8.4 Hz, C6H4), 4.14 (s, 5H, Cp), 4.10 (m, 2H, substituted Cp), 3.95 (m, 2H, substituted Cp), 3.32 and 3.78 (s, s, 3H, 3H, 0-Me), 2.56 (q, 2H, J - 7.4 Hz, -CHz-CH3), 1.02 ( t , 3 H , J = 7 . 3 Hz , -CH=-CH3 ) .
1.6 . Preparation of l,l-bis(4-hydroxyphenyl)-2-ferrocenyl-1-butene 0.55 g (1.28 mmol) of 1,1-bis(4-methoxyphenyl)-2-ferrocenyl-1-butene is dissolved in 5 ml of dichloromethane under an argon atmosphere. The solution is cooled to -78°C and then 0.3 ml (2.84 mmol) of BBr3 is added. After complete addition, the cold bath is removed and stirring is maintained for 30 minutes. The reaction mixture is then poured into ice-cold water.
After stirring for 10 minutes, NaCl is added to saturation and the product is extracted with dichloromethane (4 times 40 ml). The organic phase is first washed with water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GF2;~ silica gel plates with a 3/2 ether/pentane mixture as eluent.
0.43 g of the desired compound is obtained (RF - 0.4;
yield = 79~).
Chemical formula: Cz6H~aO2Fe Mass: 424 1H NMR (200 MHz, CDC13) : b 7.07 and 6.68 (d, d, 4H, J = 8.6 Hz, C6H4) , 6.92 and 6.80 (d, d, 4H, J = 8.5 Hz, C6H4), 4.88 and 4.42 (s, s, H, H, 2 OH), 4.11 (s, 5H, Cp), 4.08 (m, 2H, substituted Cp), 3.91 (m, 2H, substituted Cp), 2.58 (q, 2H, J = 7.5 Hz, -CHZ-CH3), 1.02 (t, 3H, J = 7.5 Hz, -CHZ-CH3) .
1.7: Production of the "trans" and °cis" isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane A sodium ethoxide solution is first prepared by reacting 0.120 g (5.2 mmol) of sodium with 20 ml of ethanol. 0.450 g (1.06 mmol) of 1,1-bis(4-hydroxyphenyl)-2-ferrocenyl-1-butane, dissolved in 10 ml of ethanol, is then added to this solution. After stirring for 1 hour at 80°C, 0.302 g (2.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride is added and the mi:cture is heated at reLlu:c ~or 3 hours. The solution is then allowed to cool to room temperature.
.-:rdrolysis is carried out with 100 m? of water and the product is e:<tracted with ether (4 times 50 ml) . The S orga:~ic phase is first washed wits. water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60Gr'~;;
silica gel places wi tz a 1/9 (C~ ;) ~N/ch'_orofor:,l mi:cture as eluent.
1.0 0.280 g of the mixture of the "trays" isomer and of the "cis" isomer of 1-[4-(2-dimethyla~-ninoethoxy)phenyl]-1-(4-hydro:cyphenyl)-2-ferrocenyl-1-butane is first obtained ('field = 53~).
The second, more polar, fraction corresponds to 15 1,1-bis[4-(2-dimethylaminoethoxy)phenyl]-2-ferrocenyl-1-butane (0.050 g; Yield = 9.5~).
1.8: Separation of the "traps" and "cis" isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane 20 The mixture of the two isomers obtained above is dissolved in an ether/hexane (5/1) mixture and the solution obtained is left in a refrigerator overnight.
As the solubility in ether of the "cis" isomer is lower than that of the "traps" isomer, the "cis"
2.'~ isomer crystallizes first after gentle evaporation of the solvent. The crystals of the "cis" isomer are isolated and the mother liquors are recooled in the freezer compartment (-15°C) of the refrigerator for one day. The "traps" isomer then crystallizes in its turn in the form of fine needles.
EXAMPLE 2: Characterization of the "traps" and "cis"
isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane 2.1: Chemical formula and molar mass 3 5 Chemical formula : C3oH330zNFe Molar mass: 495.4 2.2: 1H NI~t spectrometric data The iH NMR spectra of the two "traps" and "cis"
isomers were recorded on a spectrometer known by the Trade-mark BRUCKERTM
AC200 MHz ~:. d;-Di~ISO (Janssen) , because this solvent does not bpi.~.g about isomeriza~ion o~ the two isomers.
The ':: ~'~I~ val ues o~ t, '~e tNo isomers aye as follows:
S " .
"Traps =sourer:
~: 9.34 (s, 1H, OH), 0'.97 and 6.71 (d, d, 4H, J - 8.7 Hz, C;-~-OH) , 0.89 and 6.80 (d, d, 4H, J - 8.5 Hz, C;L-L~_ C=~) , 4.11 (s, 3~, Cp) , 4.07 (:,1, 2H, substituted Cp) 3.99 (t, 2 H, J - 6.0 Hz, 0-CH_'r , 3 .80 (m, 2H, substituted Ca), 2.60 (t, 2H, J - 6.0 Hz, N-CHz), 2.49 ( mas:ced by t he DMSO s ignal , 2 H, -CH~-CH3 )_~ 2 . 2 0 ( s , 6H, NMe~) , 0.98. (t, 3::, J - 7.3 Hz, -CHz-CHI) .
"Cis" isomer:
8: 9.29 (s, 1H, OH), 7.08 and 6.89 (d, d, 4H, J = 8.5 l.i Hz, C;HQ-OCH~) , 0'.80 and 6.63 (d, d, 4H, J = 8.4 Hz, C6H~-OH), 4.11 (s, SH, Cp), 4.08 (m, 2H, (t, 2H, J - 6.0 Hz, N-CH2), 2.49 (masked by the DMSO
signal, 2H, -CHI-CHI) , 2.23 (s, 6H, NMez) , 0.98 (t, 3H, J = 7 . 3 Hz , -CHZ-CH3 ) .
2C~ 2.3: Melting points The melting points of the "traps" and "cis"
isomers were determined using a Kofler bench. They are respectively 93-94°C for the "traps" isomer and 181°C
for the "cis" isomer.
25 EXAMPLE 3: Cytotoxic activity of the "traps" and "cis"
isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane The evaluation of the cytotoxicity of the "traps" and "cis" isomers of 1-[4-(2 30 dimethylaminoethoxy)phenyl -1-(4-hydroxyphenyl)-2 ferrocenyl-1-butane has formed the subject of tests on human cell lines derived from a pleural effusion from a mammary adenocarcinoma (MCF-7 ATCC HTB line) and one of its variants (MCF-7P line).
35 These cells were precultured in Dulbecco's MEM
medium, to which has been added 10~ fetal calf serum, in a moist atmosphere ~(90~ relative humidity) comprising S~ COz. In the exponential growth phase, these cells were trypsinated and subcultured in 24-well plates, the wells having a capacity of 1 ml, in the proportion of 2 x 105 cells per well.
After incubating for 3 days, the test compounds were added at tze appropriate doses and the plates were S incubated for 5 days.
On conc'_usion of this incubation, the cell viability of the cultures was determined using the so-called "MTT" tes~. which comprises the addition to each well of 20 ul of a solution containing S mg of 3- (4, 5-dimethylthiazol-2-yl)-2,S-diphenyltetrazolium bromide (MTT) in 1 ml of PBS buffer, followed by allowing the plates to incubate for 1 hour at 37°C under atmospheric conditions identical to those defined above. MTT is metabolized in living cells into an insoluble blue 1S compound (formazan).
On conclusion of this incubation, the wells are washed using PBS in order to remove the MTT and the residual formazan crystals are taken up in 1 ml of DMSO. The formazan concentration for each well is read by photometry at a wavelength of 550 nm and compared with a control corresponding to medium incubated in the presence of MTT but in the absence of cells.
Figures 1A and 1B show the results of the cytotoxicity tests carried out respectively with the "cis" isomer (Figure lA) and the "trans" isomer (Figure 1B) of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4 hydroxyphenyl)-2-ferrocenyl-1-butene on the two cell lines shown above. These results are expressed as fractions of surviving cells as a function of the doses of the compound tested.
By way of comparison, Figure 2 shows the results obtained on carrying out the same tests with tamoxifen under the same conditions.
The 50~ inhibitory doses (ICSO), expressed in umol and calculated with respect to the points in Figures lA, 1B and 2 between 5 x 10-' and 10-5 mol/1, are presented in Table 1 below.
The ':: ~'~I~ val ues o~ t, '~e tNo isomers aye as follows:
S " .
"Traps =sourer:
~: 9.34 (s, 1H, OH), 0'.97 and 6.71 (d, d, 4H, J - 8.7 Hz, C;-~-OH) , 0.89 and 6.80 (d, d, 4H, J - 8.5 Hz, C;L-L~_ C=~) , 4.11 (s, 3~, Cp) , 4.07 (:,1, 2H, substituted Cp) 3.99 (t, 2 H, J - 6.0 Hz, 0-CH_'r , 3 .80 (m, 2H, substituted Ca), 2.60 (t, 2H, J - 6.0 Hz, N-CHz), 2.49 ( mas:ced by t he DMSO s ignal , 2 H, -CH~-CH3 )_~ 2 . 2 0 ( s , 6H, NMe~) , 0.98. (t, 3::, J - 7.3 Hz, -CHz-CHI) .
"Cis" isomer:
8: 9.29 (s, 1H, OH), 7.08 and 6.89 (d, d, 4H, J = 8.5 l.i Hz, C;HQ-OCH~) , 0'.80 and 6.63 (d, d, 4H, J = 8.4 Hz, C6H~-OH), 4.11 (s, SH, Cp), 4.08 (m, 2H, (t, 2H, J - 6.0 Hz, N-CH2), 2.49 (masked by the DMSO
signal, 2H, -CHI-CHI) , 2.23 (s, 6H, NMez) , 0.98 (t, 3H, J = 7 . 3 Hz , -CHZ-CH3 ) .
2C~ 2.3: Melting points The melting points of the "traps" and "cis"
isomers were determined using a Kofler bench. They are respectively 93-94°C for the "traps" isomer and 181°C
for the "cis" isomer.
25 EXAMPLE 3: Cytotoxic activity of the "traps" and "cis"
isomers of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-1-butane The evaluation of the cytotoxicity of the "traps" and "cis" isomers of 1-[4-(2 30 dimethylaminoethoxy)phenyl -1-(4-hydroxyphenyl)-2 ferrocenyl-1-butane has formed the subject of tests on human cell lines derived from a pleural effusion from a mammary adenocarcinoma (MCF-7 ATCC HTB line) and one of its variants (MCF-7P line).
35 These cells were precultured in Dulbecco's MEM
medium, to which has been added 10~ fetal calf serum, in a moist atmosphere ~(90~ relative humidity) comprising S~ COz. In the exponential growth phase, these cells were trypsinated and subcultured in 24-well plates, the wells having a capacity of 1 ml, in the proportion of 2 x 105 cells per well.
After incubating for 3 days, the test compounds were added at tze appropriate doses and the plates were S incubated for 5 days.
On conc'_usion of this incubation, the cell viability of the cultures was determined using the so-called "MTT" tes~. which comprises the addition to each well of 20 ul of a solution containing S mg of 3- (4, 5-dimethylthiazol-2-yl)-2,S-diphenyltetrazolium bromide (MTT) in 1 ml of PBS buffer, followed by allowing the plates to incubate for 1 hour at 37°C under atmospheric conditions identical to those defined above. MTT is metabolized in living cells into an insoluble blue 1S compound (formazan).
On conclusion of this incubation, the wells are washed using PBS in order to remove the MTT and the residual formazan crystals are taken up in 1 ml of DMSO. The formazan concentration for each well is read by photometry at a wavelength of 550 nm and compared with a control corresponding to medium incubated in the presence of MTT but in the absence of cells.
Figures 1A and 1B show the results of the cytotoxicity tests carried out respectively with the "cis" isomer (Figure lA) and the "trans" isomer (Figure 1B) of 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4 hydroxyphenyl)-2-ferrocenyl-1-butene on the two cell lines shown above. These results are expressed as fractions of surviving cells as a function of the doses of the compound tested.
By way of comparison, Figure 2 shows the results obtained on carrying out the same tests with tamoxifen under the same conditions.
The 50~ inhibitory doses (ICSO), expressed in umol and calculated with respect to the points in Figures lA, 1B and 2 between 5 x 10-' and 10-5 mol/1, are presented in Table 1 below.
TABLE 1:
COMPOUND TESTED ICSO (umol) "Cis" derivative 3.4 5.6 "Trans" derivative 4.9 2 Tamoxifen 6.4 7.2 The lower the 50~ inhibitory dose, the greater the cytotoxic activity and the results expressed in Table 1 show that the "cis" and "trans" isomers of 1-[4-(2-dimethyla~-ninoethoxy)phenyl]-1-(4-hydroxy-phenyl)-2-fe=rocenyl-1-butene exhibit, with respect to the two cell lines tested, a cytotoxic activity which is greatsr than that of tamoxifen.
COMPOUND TESTED ICSO (umol) "Cis" derivative 3.4 5.6 "Trans" derivative 4.9 2 Tamoxifen 6.4 7.2 The lower the 50~ inhibitory dose, the greater the cytotoxic activity and the results expressed in Table 1 show that the "cis" and "trans" isomers of 1-[4-(2-dimethyla~-ninoethoxy)phenyl]-1-(4-hydroxy-phenyl)-2-fe=rocenyl-1-butene exhibit, with respect to the two cell lines tested, a cytotoxic activity which is greatsr than that of tamoxifen.
Claims (17)
1. A compound of general Formula (I):
wherein:
the -O(CH2)n Z group is in the meta or para position with respect to the -CR3=CR4R5 group, n represents an integer of between 2 and 10, and Z
represents a basic or polar ligand which is selected from -NR1R2 groups, wherein R1 and R2, which are identical or different, represent an unsubstituted C1 to C6 alkyl group or a C1 to C6 alkyl group which is substituted by at least one halogen atom, or a -SR1 group, or a -SOR1 group, or a -SO2R1 group, wherein R1 has the same meaning as above, and wherein:
either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C1 to C3 alkyl group, or by at least one C1 to C3 alkoxy group, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively a C1 to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and R5 represents a metallocene group, which corresponds to the general Formula (II):
wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, or an oxidized form thereof, or R3 represents a metallocene group, as hereinabove defined, and R5 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one of a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN
group, or alternatively a C1 to C3 alkyl group, in all its stereoisomeric forms and its salts.
wherein:
the -O(CH2)n Z group is in the meta or para position with respect to the -CR3=CR4R5 group, n represents an integer of between 2 and 10, and Z
represents a basic or polar ligand which is selected from -NR1R2 groups, wherein R1 and R2, which are identical or different, represent an unsubstituted C1 to C6 alkyl group or a C1 to C6 alkyl group which is substituted by at least one halogen atom, or a -SR1 group, or a -SOR1 group, or a -SO2R1 group, wherein R1 has the same meaning as above, and wherein:
either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C1 to C3 alkyl group, or by at least one C1 to C3 alkoxy group, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively a C1 to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and R5 represents a metallocene group, which corresponds to the general Formula (II):
wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, or an oxidized form thereof, or R3 represents a metallocene group, as hereinabove defined, and R5 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one of a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN
group, or alternatively a C1 to C3 alkyl group, in all its stereoisomeric forms and its salts.
2. The compound as claimed in claim 1, which corresponds to the specific Formula (I-a):
wherein:
the -O(CH2)2 Z group is the para position with respect to the -CR3=CR4R5 group, and Z represents an -NR1R2 group, wherein R1 and R2, which are identical or different, represent a methyl group, or an ethyl group, or alternatively Z
represents an N-pyrrolidino group, R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by a hydroxyl group or by a methoxy group, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively, an ethyl group, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of said selected metal.
wherein:
the -O(CH2)2 Z group is the para position with respect to the -CR3=CR4R5 group, and Z represents an -NR1R2 group, wherein R1 and R2, which are identical or different, represent a methyl group, or an ethyl group, or alternatively Z
represents an N-pyrrolidino group, R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by a hydroxyl group or by a methoxy group, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively, an ethyl group, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of said selected metal.
3. The compound as claimed in claim 2, wherein R1 and R2 represent a methyl group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl group and R4 represents an ethyl group,
4. As the compound as claimed in claim 3, 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxy-phenyl)-2-ferrocenyl-1-butene.
5. As the compound as claimed in claim 4, the "trans" isomer of 1-[4-(2-dimethylaminoethoxy)phenyl]-(4-hydroxyphenyl)-2-ferrocenyl-1-butene.
6. The compound as claimed in claim 2, wherein R1 and R2 represent a methyl group, R3 represent a phenyl group and R4 represents an ethyl group.
7. As the compound as claimed in claim 6, 1-[4-(2-dimethylaminoethoxy)phenyl)-1-phenyl-2-ferrocenyl-1-butene.
8. The compound as claimed in claim 1, wherein:
the -O(CH2)n Z group is in the para position with respect to the -CR3=CR4R5 group, n is equal to 2 and Z represents an N-pyrrolidino group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl, or by a C1 to C3 alkoxy group, and R4 represents a C2 alkyl group, the end carbon of which is bonded to the carbon which is situated in the 2 position of the phenyl group of R3, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of said metal.
the -O(CH2)n Z group is in the para position with respect to the -CR3=CR4R5 group, n is equal to 2 and Z represents an N-pyrrolidino group, R3 represents a phenyl group which is substituted in the para position by a hydroxyl, or by a C1 to C3 alkoxy group, and R4 represents a C2 alkyl group, the end carbon of which is bonded to the carbon which is situated in the 2 position of the phenyl group of R3, and M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, or an oxidized form of said metal.
9. A process for the preparation of a compound as claimed in claims 1 to 8, which comprises:
a) reacting a compound of general Formula (IV):
wherein:
the -O(CH2)n Z group is in the meta or para position with respect to the -CR3=R4R5 group, n represents an integer of between 2 and 10, and Z represents a basic or polar ligand which is selected from -NR1R2 groups, wherein R1 and R2, which are identical or different, represent an unsubstituted C1 to C6 alkyl group or a C1 to C6 alkyl group which is substituted by at least one halogen atom, or at least one heterocyclic group containing a nitrogen atom, or at least one -OR1 group, or at least one -group, or at least one -SOR1 group, or at least one -SO2R1 group, wherein R1 has the same meaning as above, and wherein:
either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group or by at least one C1 to C3 alkyl group, or by at least one C1 to C3 alkoxy group, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively a C1 to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and R5 represents a bromine atom, or R3 represents a bromine atom, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively a C1 to C3 alkyl group, and R5 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C1 to C3 alkyl group, or by at least one C1 to C3 alkoxy group, with a cyclopentadienyl metal salt, in order to substitute the bromine atom by a cyclopentadiene group;
b) reacting the compound obtained in Stage a) with a strong base, in order to form a cyclopentadienyl anion; and c) reacting the compound obtained in Stage b) with an organometallic compound of the Formula:
wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, and X represents a halogen atom which is selected from the group consisting of chlorine, bromine or iodine.
a) reacting a compound of general Formula (IV):
wherein:
the -O(CH2)n Z group is in the meta or para position with respect to the -CR3=R4R5 group, n represents an integer of between 2 and 10, and Z represents a basic or polar ligand which is selected from -NR1R2 groups, wherein R1 and R2, which are identical or different, represent an unsubstituted C1 to C6 alkyl group or a C1 to C6 alkyl group which is substituted by at least one halogen atom, or at least one heterocyclic group containing a nitrogen atom, or at least one -OR1 group, or at least one -group, or at least one -SOR1 group, or at least one -SO2R1 group, wherein R1 has the same meaning as above, and wherein:
either R3 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group or by at least one C1 to C3 alkyl group, or by at least one C1 to C3 alkoxy group, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively a C1 to C3 alkyl group, the end carbon of which can be free or can be bonded to the carbon which is situated at the 2 position of the phenyl group of R3, and R5 represents a bromine atom, or R3 represents a bromine atom, R4 represents a hydrogen atom, or a halogen atom, or an NO2 group, or a chloroethyl group, or a CN group, or alternatively a C1 to C3 alkyl group, and R5 represents an unsubstituted phenyl group or a phenyl group which is substituted by at least one hydrogen atom, or by at least one halogen atom, or by at least one hydroxyl group, or by at least one C1 to C3 alkyl group, or by at least one C1 to C3 alkoxy group, with a cyclopentadienyl metal salt, in order to substitute the bromine atom by a cyclopentadiene group;
b) reacting the compound obtained in Stage a) with a strong base, in order to form a cyclopentadienyl anion; and c) reacting the compound obtained in Stage b) with an organometallic compound of the Formula:
wherein M represents a metal atom which is selected from Group VIII of the Periodic Classification of the chemical elements, and X represents a halogen atom which is selected from the group consisting of chlorine, bromine or iodine.
10. A process for the preparation of the compound as claimed in claims 3 to 5, which comprises:
a) subjecting a metallocene ester of Formula (V):
wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, to an addition reaction with an organolithium compound CH3-O-C6H4-Li or with an organomagnesium compound CH3-O-C6H4 MgX, wherein X represents a chlorine atom, a bromine atom or an iodine atom, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol;
b) subjecting the compound obtained in Stage a) to a demethylation reaction;
and c) subjecting the compound obtained in Stage b) to an alkylation reaction with sodium ethoxide and the hydrochloride of 2-dimethylaminoethyl chloride.
a) subjecting a metallocene ester of Formula (V):
wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, to an addition reaction with an organolithium compound CH3-O-C6H4-Li or with an organomagnesium compound CH3-O-C6H4 MgX, wherein X represents a chlorine atom, a bromine atom or an iodine atom, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol;
b) subjecting the compound obtained in Stage a) to a demethylation reaction;
and c) subjecting the compound obtained in Stage b) to an alkylation reaction with sodium ethoxide and the hydrochloride of 2-dimethylaminoethyl chloride.
11. The process as claimed in claim 10, which includes the preliminary step of the preparation of the metallocene ester of Formula (V) by esterification of the corresponding metallocenylacetic acid, followed by an alkylation reaction of the carbon in the position a to the metallocenyl ring of said ester.
12. The process as claimed in claims 9 to 11, which includes the additional step of the separation of the "cis" and "trans" isomers of the compound so-obtained.
13. The process for the preparation of the compound as claimed in claim 6 or claim 7, which comprises:
a) reacting a metallocenic acid chloride of Formula (VI):
wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, with diphenylzinc, in order to substitute the chlorine atom by a phenyl group; and b) subjecting the compound which is obtained in Stage a) to an addition reaction with an organolithium compound (CH3)2-N-(CH2)2-O-C6H4 Li, or with an organomagnesium compound (CH3)2-N-(CH2)2-O-C6H4-MgX, wherein X
represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol.
a) reacting a metallocenic acid chloride of Formula (VI):
wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, with diphenylzinc, in order to substitute the chlorine atom by a phenyl group; and b) subjecting the compound which is obtained in Stage a) to an addition reaction with an organolithium compound (CH3)2-N-(CH2)2-O-C6H4 Li, or with an organomagnesium compound (CH3)2-N-(CH2)2-O-C6H4-MgX, wherein X
represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol.
14. The process as claimed in claim 13 including the additional step of the separation of the "cis" and "trans" isomers of the compound so-obtained.
15. A process for the preparation of the compound as claimed in claim 8, which comprises:
a) reacting a tetralone of Formula (VII):
wherein R6 represents a hydrogen atom or a C1 to C3 alkyl group, with an organolithium compound or with an organomagnesium compound wherein X represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol;
b) subjecting the compound which is obtained in Stage a) to a bromination reaction, in order to obtain the compound of Formula (VIII):
c) subjecting the compound of Formula (VIII) thus obtained to a coupling reaction with an organometallic compound of the Formula:
wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, and Y represents a lithium atom, a copper atom, an SnBu3 group or an HgCl group.
a) reacting a tetralone of Formula (VII):
wherein R6 represents a hydrogen atom or a C1 to C3 alkyl group, with an organolithium compound or with an organomagnesium compound wherein X represents a halogen atom which is selected from the group consisting of chlorine, bromine and iodine, which results in the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol;
b) subjecting the compound which is obtained in Stage a) to a bromination reaction, in order to obtain the compound of Formula (VIII):
c) subjecting the compound of Formula (VIII) thus obtained to a coupling reaction with an organometallic compound of the Formula:
wherein M represents a metal atom which is selected from the group consisting of iron, ruthenium and osmium, and Y represents a lithium atom, a copper atom, an SnBu3 group or an HgCl group.
16. A medicament comprising either at least one of the compounds of Formula (I) as claimed in claims 1 to 8, or one of its salts, or a pharmaceutical composition, comprising at least one of the compound of Formula (I) as claimed in claims 1 to 8 or one of its salts, as an active constituent in an effective amount in combination with a pharmacologically-acceptable vehicle.
17. A use of the compound of Formula (I) or of one of its salts as claimed in claims 1 to 8 for the production of an antitumour medicament.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR94/12151 | 1994-10-12 | ||
| FR9412151A FR2725720B1 (en) | 1994-10-12 | 1994-10-12 | METALLOCENIC DIARYLETHYLENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID DERIVATIVES |
| CA002202169A CA2202169A1 (en) | 1994-10-12 | 1995-10-11 | Metallocenic diarylethylene derivatives, methods for their preparation and pharmaceutical compositions containing same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002202169A Division CA2202169A1 (en) | 1994-10-12 | 1995-10-11 | Metallocenic diarylethylene derivatives, methods for their preparation and pharmaceutical compositions containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2235967A1 CA2235967A1 (en) | 1996-04-25 |
| CA2235967C true CA2235967C (en) | 2001-12-18 |
Family
ID=25679228
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002235967A Expired - Fee Related CA2235967C (en) | 1994-10-12 | 1995-10-11 | Diarylethylene metallocene derivatives, their processes of preparation and pharmaceutical compositions containing said derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2235967C (en) |
-
1995
- 1995-10-11 CA CA002235967A patent/CA2235967C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2235967A1 (en) | 1996-04-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1088950A (en) | Triphenylalkene derivatives | |
| EP0099148B1 (en) | Piperazine derivatives, processes for their preparation and pharmaceutical preparations containing them | |
| FI62829C (en) | FOERFARANDE FOER FRAMSTAELLNING AV FENOLETRAR ANVAENDBARA SAOSOM CEILING MODEL | |
| JPH037239A (en) | Novel production of alkane and alkene derivatives | |
| JP5747394B2 (en) | Proteasome inhibitor | |
| JP2795677B2 (en) | Ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes | |
| US4605672A (en) | Diethylaminoalkoxybenzhydrol derivatives, process for their preparation and pharmaceutical compositions containing them | |
| US2870150A (en) | Morpholine ethers | |
| CA2235967C (en) | Diarylethylene metallocene derivatives, their processes of preparation and pharmaceutical compositions containing said derivatives | |
| KR100383847B1 (en) | Diarylethylene Metallocene Derivatives, Methods of Making Them, and Pharmaceutical Compositions Containing These Derivatives | |
| MXPA97002671A (en) | Diarilethylene metalocyanic derivatives, preparation methods and pharmaceutical compositions containing these derivatives | |
| US5863911A (en) | Diarylethylene metallocene derivatives, their processes of preparation and pharmaceutical compositions containing said derivatives | |
| US4206213A (en) | Dithienylalkylamines and process for their production | |
| JPS5824567A (en) | Novel imidazole compound, manufacture and antimycotic | |
| HU193268B (en) | Process for preparing novel substituted alkane and alkene derivatives | |
| Ruenitz et al. | Substituted-vinyl hydroxytriarylethylenes, 1-[4-[2-(diethylamino) ethoxy] phenyl]-1-(4-hydroxyphenyl)-2-phenylethylenes: synthesis and effects on MCF 7 breast cancer cell proliferation | |
| US3506653A (en) | Non-steroid hormonal agents | |
| US5658927A (en) | Diphenylcyclopropyl analogs | |
| US4508926A (en) | 4-Hydroxy-benzhydrols, process for their preparation and pharmaceutical compositions containing them | |
| EP0115203B1 (en) | Benzhydrylpiperazine derivatives, process for their preparation and pharmaceutical compositions containing them | |
| US6610705B1 (en) | Process for the preparation of diaryl naphthyl methanes | |
| Dimmock et al. | Synthesis of Oximes, Aziridines, and Allyl Alcohols Derived from Substituted l-Phenyl-l-nonen-3-ones as Potential Cytotoxic and Antitumor Agents | |
| US2870147A (en) | Morpholine ethers | |
| EP0006961A1 (en) | New phenylethylamines, process for their preparation, and pharmaceutical compositions containing them | |
| Heinzelman et al. | Physiologically active amines. Tertiary amines and quaternary salts related to β-(o-methoxyphenyl)-isopropyl-N-methylamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |