MXPA97006015A

MXPA97006015A - Novedous inhibitors of farnesil transferase, supreparation and pharmaceutical compositions chelos contie

Info

Publication number: MXPA97006015A
Application number: MXPA/A/1997/006015A
Authority: MX
Inventors: Clerc Francoisfrederic
Original assignee: Rhonepoulenc Rorer Sa
Priority date: 1995-02-09
Filing date: 1997-08-06
Publication date: 1998-07-03

Abstract

The present invention describes novel inhibitors of farnesyl transferase, of general formula (I), its preparation and the pharmaceutical compositions containing them. In the general formula (I), R1 represents YS-A1- (Y = hydrogen atom, amino acid residue, fatty acid residue, alkyl or alkoxycarbonyl radical, or radical R4-S-, in which R4 represents an alkyl radical which contains from 1 to 6 carbon atoms, optionally substituted by a phenyl radical, or radical of general formula (II), in which A1, X1, Y1, R2, R'2, X2, Y2, X, R3, R'3 and R are as defined below, and A1 = alkylene radical containing from 1 to 4 carbon atoms, optionally substituted in alpha of the group> C (X1) (Y1) by an amino, alkylamino, alkanoylamino, alkoxycarbonylamino radical), X1 and Y1 represents each a hydrogen atom, or form, together with the carbon atom to which they are attached, a group > C = O, R2 represents a straight or branched chain alkyl radical, containing from 1 to 4 carbon atoms, optionally substituted by a cyclohexyl radical, R'2 represents hydrogen or alkyl, X2 and Y2 each represent a hydrogen atom, or they form together with the carbon atom to which a group is attached > C = O, R3 represents an alkyl radical containing from 1 to 4 carbon atoms, optionally substituted by hydroxy, alkoxy, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl, it being clear that, when R3 represents an alkyl radical substituted by a hydroxy radical, R3 it can form with the carboxy radical in alpha a lactone, R'3 represents hydrogen or alkyl, X represents an oxygen or sulfur atom, and R represents a hydrogen atom, or an optionally substituted alkyl radical, or an optionally substituted phenyl radical. These innovative products have anti-cancer properties

Description

NOVEDOUS INHIBITORS OF FARNESIL TRANSFERASA, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT THE CONTAINING DESCRIPTION OF THE INVENTION The present invention relates to novel inhibitors of farnesyl transferase, of the general formula: to its preparation, and to the pharmaceutical compositions containing them. The inhibition of farnesyl transferase and, consequently, farnesylation of the ras protein, blocks the ability of the mutated ras protein to transform normal cells into cancer cells. The C-terminal sequence of the ras gene containing the sequence "CAAX" or "Cis-Aaa? -Aaa2-Xaa", in which? Aa represents an aliphatic amino acid and Xaa represents any amino acid. It is known that tetrapeptides with a CAAX sequence can inhibit farnesylation of the ras protein. For REF: 25110, PCT application WO 91/16340 and EP 0 461 869 describe peptides inhibitors of farnesyl transferase Cis-Aaai-Aaa? -Xaa which are represented more particularly by peptides Cis-Val- Leu-Ser, Cis-Val-Ile-Met and Cis-Val-Val-Met, which manifest their inhibitory activity at concentrations close to 10"6 M or 10" 7 M. It has now been found, and is what the object of the present invention, that the peptides of the general formula (I) manifest their inhibitory activity (IC50) at concentrations of the order of 10"8 M. In the general formula (I), Ri represents a radical of the general formula YS-Ai -, in which 'i represents a hydrogen atom, or an amino acid residue, or a fatty acid residue, or an alkyl or alkoxycarbonyl radical, or a radical R4-S-, in which R4 represents an alkyl radical which contains from 1 to 6 carbon atoms, optionally substituted by a phenyl radical, or a radical of general formula (II) wherein Ai, X, Yi, R2, R '?, X2 Y2,, RJ, R' 3 and R are defined as follows, and Ai represents a straight or branched chain alkylene radical, containing from 1 to 4 carbon atoms, optionally substituted in a of the group > C (X?) (Y-) by an amino radical, alkylamino containing from 1 to 4 carbon atoms, alkanoylamino containing from 1 to 4 carbon atoms, or alkoxycarbonylamino whose alkyl part contains from 1 to 4 carbon atoms, Xi and Yi each represent a hydrogen atom, or form, together with the carbon atom to which they are attached, a group > C = 0, R2 represents a straight or branched chain alkyl radical, containing from 1 to 4 atoms of carbon, optionally substituted by a cyclohexyl radical, R'2 represents a hydrogen atom or a straight or branched chain alkyl radical, containing from 1 to 6 carbon atoms, X2 and Y2 each represent a hydrogen atom, or form together with the carbon atom to which a group is attached> C = 0, R3 represents a straight or branched chain alkyl radical, containing 1 to 4 carbon atoms, optionally substituted by hydroxy, alkoxy containing 1 to 4 carbon atoms; to 4 carbon atoms, mercapto, alkylthi or containing 1 to 4 carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms, or alkylsulfonyl containing 1 to 4 carbon atoms, it being clear that, when Rj represents an alkyl radical substituted by a hydroxy radical, R3 can form a lactone with the carboxy radical in a, R '3 represents a hydrogen atom or a straight or branched chain alkyl radical, containing from 1 to 6 carbon atoms, X represents an oxygen or sulfur atom, and R represents a hydrogen atom, or an alkyl radical optionally substituted by an alkoxy radical containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms, alkylsulfinyl containing from 1 to 4 carbon atoms, alkylsulfonyl containing from 1 to 4 carbon atoms, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, alkylamino containing from 1 to 4 carbon atoms, or dialkylamino, of which each alkyl part contains from 1 to 4 carbon atoms; carbon, or a phenyl radical optionally substituted by one or more atoms or radicals, identical or different, selected from the halogen atoms and the alkyl, alkoxy, alkylthio or alkanoyl radicals containing from 1 to 4 carbon atoms.

More particularly, Ri represents a radical of general formula YS-Ai.-, in which Y represents a hydrogen atom, or a lysine residue, or a fatty acid residue containing up to 20 carbon atoms, and A i represents a ethylene or propylene radical optionally substituted by an amino radical, Xi and Yi each represent a hydrogen atom, or form, together with the carbon atom to which they are attached, a group > C = 0, R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical, R'2 represents a hydrogen atom or a methyl radical, X2 and Y2 each represent a hydrogen atom, or form together with the atom of carbon to which a group is united > C = 0, R3 represents a methyl or ethyl radical substituted by a hydroxy, methoxy, mercapto, methylthio, methylsulfinyl or methylsulfonyl radical, R '3 represents a hydrogen atom or a methyl radical, X represents an oxygen atom, and R represents a hydrogen atom, or an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by an alkoxy radical, or a phenyl radical.

Even more particularly, R: represents a radical of general formula YSA-, in which Y represents a hydrogen atom, and Ai represents an ethylene or propylene radical optionally substituted by an amino radical, Xi and Yi each represent a hydrogen atom , or form, together with the carbon atom to which they are attached, a group > C = 0, R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical, R'2 represents a hydrogen atom, X2 and Y2 each represent a hydrogen atom, or form together with the carbon atom to which A group is united > C = 0, R3 represents a methyl or ethyl radical substituted by a hydroxy, methoxy, mercapto, or methylthio radical R '3 represents a hydrogen atom, and R represents a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms. Very particularly interesting are the products of general formula (I) in which Ri represents a 2- ercaptoethyl or l-amino-2-mercaptoethyl radical, Xi and Yi each represent a hydrogen atom, or form, together with the carbon to which they are united, a group > C = 0, R 2 represents an isopropyl radical, X 2 and Y 'each represent a hydrogen atom, or form together with the carbon atom to which a group is attached > C = 0, R'2 represents a hydrogen atom, R represents a 2-methylthioethio or 2-methylsulfinylethyl radical, R '3 represents a hydrogen atom, and R represents a hydrogen atom. The present invention also relates to the stereoisomeric forms of the products of general formula (I). The amino acid residues represented by R? C (X?) (Y :), R2CH (NR'2) [C (X2) (Y2)] and R3CH (NR '3) CO-OH have preferably the configuration of the natural amino acids.

The present invention also relates to the mineral or organic salts, as well as to the esters of the products of general formula (I). According to the invention, the novel products of general formula (I) can be obtained by solid phase synthesis, using a "9-fluorenylmethoxycarbonyl (FMOC)" synthesis strategy. In this case, the thiol groups are protected with trityl or acetamidomethyl groups, the amino functions with Boc groups (t-butoxycarbonyl), and the acid functions in the form of tert-butyl ester, the alcohol functions by tert-butyl groups, and the amide and imidazole functions by trityl groups. The synthesis can be carried out on a resin confined in extraction syringes, in solid phase of 3 cm3 in high density polyethylene, provided with Teflon filters. The syringes are placed on a two-way Teflon valve, and closed with a single-use high density polyethylene flap stopper. The agitation of the syringes is carried out on a rotary device for hemolysis tubes. The washing and filtering operations are conducted on a solid phase extraction work station. The syntheses are then carried out on 50 μmol of resin. The couplings of the amino acids are carried out by treating the resin with 250 μmol of the amino acid suitably protected in the presence of 250 μmol of 2- (lH-benzotriazol-1-yl) -1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 250 μmol of N-hydroxybenzotriazole and 750 μmol of diisopropylethylamine in 1. 2 cmJ of a mixture of N-methylpyrrolidone-2 (NMP) / dimethylformamide (1/1 by volume). The deprotection of the FMOC group is carried out by 3 successive treatments of the resin 2 times for 1 minute, and then for 20 minutes with 2 cm3 of piperidine in 2% (v / v) solution in the NMP. For example, Cis- (Nme) Val- [cis-3-phenyl-DL-prolyl] -Met can be prepared in the following manner: 50 μmoles of Fmoc-Met-chlorotritil resin are successively subjected to the following treatments: FMOC deigrupoprotection, 5 times washed with 2 cpr of NMP, FMOC-cis-3-phenyl-DL-proline coupling, washing 5 times with 2 cm3 of NMP, -deprotection of FMOC, -wash 5 times with 2 cmJ of NMP, -coupling of FMOC-N-methylvaline, -wash 5 times with 2 cm3 of NMP, -deprotection of FMOC, -wash 5 times with 2 cmJ of NMP, -coupling of FMOC-cysteine (S-trityl), -wash 5 times with 2 cm3 of NMP, -deprotection of FMOC, -wash 5 times with 2 cm3 of NMP. After the synthesis, the products are separated by treatment of the resin with 10 cm3 of a mixture of trifluoroacetic acid-phenol-ethanedithiol-thioanisole-water (40-3-1-2-2 in volumes) for 1 hour 30 minutes. The resin is then removed by filtration. The filtrate is concentrated under reduced pressure by means of a centrifugal evaporator (RC10-10 Jouan) equipped with a vane pump and with a trap at -90 ° C for 1.5 hours, the temperature of the evaporation chamber is maintained at 50 °. C. The final volume of the concentrated material is around 1 cirr. The product is then precipitated by addition of 15 cpr of a mixture of ethyl tert-butyl ether and petroleum ether (2: 1 by volume), and is then collected by centrifugation. The pellet is then solubilized in 1 cm of trifluoroacetic acid, precipitated by addition of 15 cm.sup.-1 of methyl tert.-butyl ether, and then washed with 15 cm.sup.3 of methyl tert.-butyl ether. The product is then dried under reduced pressure (0.0357 kg / cm ^, 3.5 kPa). The product is finally purified by high performance liquid chromatography (HPLC) on a Cie column of 100 angstroms (250 x 10 mm, BioRad), eluted with a gradient of acetonitrile containing 0.07% trifluoroacetic acid (by volume) in water that contained 0. 07% of trifluoroacetic acid (by volume) to a flow of 6 cm3, and then lyophilized. The products obtained are characterized by their mass spectra (electroinduction).

The introduction of the FMOC protective group onto an amino acid is effected by the action of the amino acid on the 9-fluorenylmethyl chloroformate (FMOC-chloride) in the presence of a base. The FMOC-Met-chlorotryril resin can be obtained by the reaction of 250 μmol of chlorotryl chloride resin (Novabiochepr®) with 1 mmol of FMOC-Methionine in 2 cm3 of dichloromethane and 0.5 cm of diisopropylethylamine for 30 minutes. After 2 cm3 of methanol, the reaction is continued for a further 30 minutes The resin is then washed 5 times with 4 cirr of dichloromethane, and then dried The cis- and trans-phenylproline, under the racemic form, can be obtained in the conditions described by R. Sarges and JR Tretter, J. Org. Chem., 39, 1710 (1974) .The inhibitory activity of farnesyltransferase and farnesylation of the Ras protein can be evidenced in the following test: The farnesyltransferase activity is determined by the amount of (3H) farnesyl transferred from the (3H) farnesylpyrophosphate [(3H) FPP)] to the p21 lira protein.The standard reaction mixture is composed, for a final volume d e 60 μl, 50 mM Tris-HCL, 5 mM MgCl2, 5 mM dithiothreitol, 0.2% octyl-β-D-glucopyranoside, p21 H-ras 300 picomoles, (3H) FPP) (at 61000 dpm / picomol) 4.5 picomoles. The reaction is initiated by the addition of about 5 ng of human farnesyltransferase, purified from cultures of THP1 cells. After incubation for 20 minutes at 37 ° C in microtiter plates containing 96 wells, of 1 cm3 per plate (Titer PlateMR, Beckman), the reaction was stopped by the addition of 0.4 cm3 of 0.1% SDS in methanol at 0 ° C. The mixture was then added 0.4 cc of trichloroacetic acid (TCA). at 30% in methanol. The plates were left for 1 hour on ice. The precipitated content is then retained on a Filtermat ™ glass fiber membrane, Pharmacia) with the filtration unit (Co bi Cell Harvester ™, Skatron) and rinsed with 6% trichloroacetic acid in distilled water. The membranes were dried in a microwave oven, and then impregnated with scintillation agent by Meltilex ™ hot air fusion (Pharmacia) and finally the counts in cpm were determined in a β-Plate counter (LKB). it was repeated 3 times The activity unit is defined by 1 picomol of (3H) FPP) transferred over p21 H-ras in 20 minutes.The percentages of inhibition are obtained by comparison of the tests with and without inhibitor after the deduction of the targets, the IC5o were measured from the inhibitions obtained with 9 different concentrations, using the Enzfitter or Grafit "* programs. The results obtained are summarized in Table I.

TABLE I Product Inhibitory activity IC50 Cis- (N-Me) Val- [cis-3-phenyl-DL-prolyl1 -Met 1.55 x 10"'M Cis- (N-Me) Val- [trans-3-phenyl-DL-prolyl] -Met 9.2 x 10"" M The novel peptides of the general formula (I) can be presented in the form of non-toxic and pharmaceutically acceptable salts These non-toxic salts comprise the salts with the mineral acids (hydrochloric, sulfuric, hydrobromic, phosphoric, nitric acids) , or with organic acids (acetic, propionic, succinic, maleic, hydroxymelic, benzoic, fumaric, methanesulfonic, trifluoroacetic or oxalic acids) or with mineral (soda, potash, lithium, lime) or organic bases (tertiary amines such as triethylamine, piperidine, benzylamine) according to the nature of the amino acids constituting the peptide of general formula (I) The novel peptides according to the invention, which inhibit farnesyltransferase and farnesylation of Ras proteins, are remarkable anticancer agents, which act both level of solid tumors The present invention also relates to pharmaceutical compositions containing at least one peptide of general formula (I) in association with one or more pharmaceutically acceptable diluents or adjuvants, which are inert or physiologically active. These compositions can be administered orally, parenterally or rectally. Compositions for oral administration comprise tablets, pills, powders or granules. In these compositions, the active compound according to the invention is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions may comprise substances other than diluents, for example a lubricant such as magnesium stearate. As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil can be used. These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavoring products. The compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate, can be used. These compositions may also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. The sterilization can be carried out in various ways, for example with the aid of a bacteriological filter, by incorporating sterilizing agents into the composition, or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved at the time of use in sterile water, or any other sterile injectable medium. Compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter. The compositions according to the invention are particularly useful in human therapy, in the treatment of cancers of various origins. In human therapy, the doses depend on the effect sought, the duration of treatment, and factors specific to the subject to be treated. In general, doses are included, for man, between 0.1 and 20 mg / kg per day, by intra-peritoneal route.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

CLAIMS Novel peptides of general formula di characterized in that: Ri represents a radical of general formula YSA-, in which Y represents a hydrogen atom, or an amino acid residue, or a fatty acid residue, or an alkyl or alkoxycarbonyl radical, or a radical R4-S- , in which R4 represents an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by a phenyl radical, or a radical of general formula (II) wherein Ai, Xt, Y, R2, R '?, X2 Y2 / X, 3 R'3 and R are defined as follows, and Ai represents a straight or branched chain alkylene radical, containing from 1 to 4 carbon atoms, optionally substituted in a of the group > C (X-.) (Y;) by an amino radical, alkylamino containing from 1 to 4 carbon atoms, alkanoyole containing from 1 to 4 carbon atoms, or alkoxycarbonylamino whose alkyl part contains from 1 to 4 carbon atoms; carbon, X and Yi each represent a hydrogen atom, or form, together with the carbon atom to which they are attached, a group > C = 0, R? represents a straight or branched chain alkyl radical, containing from 1 to 4 carbon atoms, optionally substituted by a cyclohexyl radical, R'2 represents a hydrogen atom or a straight or branched chain alkyl radical, containing from 1 to 6 carbon atoms, X? and Y¿- each represent a hydrogen atom, or form together with the carbon atom to which a group is attached > C = 0, R3 represents a straight or branched chain alkyl radical, containing from 1 to 4 carbon atoms, optionally substituted by hydroxy, alkoxy containing from 1 to 4 carbon atoms, mercapto, alkylthio containing from 1 to 4 carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms, or alkylsulfonyl containing 1 to 4 carbon atoms, it being clear that, when R 3 represents an alkyl radical substituted by a hydroxy radical, R 3 can form with the radical. , carboxy in an iactone, R '-, represents a hydrogen atom or a straight or branched chain alkyl radical, containing from 1 to 6 carbon atoms, X represents an oxygen or sulfur atom, and R represents an hydrogen atom, or an alkyl radical optionally substituted by an alkoxy radical containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms, alkylsulfinyl containing from 1 to 4 carbon atoms, alkylsulfonyl which It has 1 to 4 carbon atoms, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, alkylamino containing 1 to 4 carbon atoms, or dialkylamino, of which each alkyl part contains 1 to 4 carbon atoms, or a radical phenyl optionally substituted by one or more atoms or radicals, identical or different, selected from the halogen atoms and the alkyl, alkoxy, alkylthio or alkanoyl radicals containing from 1 to 4 carbon atoms. 2. Novel peptides according to claim 1, characterized in that: R: represents a radical of general formula YSA: -, in which Y represents a hydrogen atom, or a lysine residue, or a fatty acid residue containing up to 20 carbon atoms, and A: represents an ethylene radical or propylene optionally substituted by an amino radical, X; and Y each represent a hydrogen atom, or form, together with the carbon atom to which they are attached, a group > C = 0, R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical, R ': represents a hydrogen atom or a methyl radical, X2 and Y2 each represent a hydrogen atom, or form together with the atom of carbon to which a group is united > C = 0, R3 represents a methyl or ethyl radical substituted by a hydroxy, methoxy, mercapto, methylthio, methylsulfinyl or methylsulfonyl radical, R ': represents a hydrogen atom or a methyl radical, X represents an oxygen atom, and R represents a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms, optionally substituted by an alkoxy radical, or a phenyl radical. 3. Novel peptides according to claim 1, characterized in that: R represents a radical of general formula YS-Ai, in which Y represents a hydrogen atom, and A represents an ethylene or propylene radical optionally substituted by an amino radical, X and Y, each representing a hydrogen atom , or form, together with the carbon atom to which they are attached, a group > C = 0, R: represents a radical i = opropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl, R '2 represents a hydrogen atom, X2 and Y? they each represent a hydrogen atom, or they form together with the carbon atom to which a group is attached > C = 0, R3 represents a methyl or ethyl radical substituted by a hydroxy, methoxy, mercapto radical, or methylthio R '3 represents a hydrogen atom, and R represents a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms. 4. Novel peptides according to claim 1, characterized in that Ri represents a 2-mercaptoethyl or

l-amino-2-mercaptoethyl radical, Xi and Yi each represent a hydrogen atom, or form, together with the carbon to which they are united, a group > C = 0, R2 represents an isopropyl radical, X2 and Y2 each represent a hydrogen atom, or form together with the carbon atom to which a group is attached > C = 0, R '-. represents a hydrogen atom, R3 represents a 2-methylthioethyl or
2-methylsulfinylethyl radical, R'3 represents a hydrogen atom, and R represents a hydrogen atom. 5. Pharmaceutical composition characterized in that it contains a sufficient amount of a peptide according to any of claims 1 to 4 in association with one or more pharmaceutically acceptable, inert or physiologically active diluents or adjuvants. SUMMARY OF THE INVENTION The present invention describes novel inhibitors of farnesii transferase, of general formula (I), its preparation and the pharmaceutical compositions containing them. In the general formula (I), R-. represents YSAL- (Y = hydrogen atom, amino acid residue, fatty acid residue, alkyl or alkoxycarbonyl radical, or radical R4-S-, in which R4 represents an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by a phenyl radical, or radical of general formula (II) in which A-, X-, Y-, R2, R ';, X ?, Y :, X, R3, R' 3 and R are as defined below, and -.- = alkylene radical containing from 1 to 4 carbon atoms, optionally substituted in a of the group> C (X) (Y- by an amino, alkylamino, alkanoylamino, alkoxycarbonylamino radical) , X: and Y- each represent a hydrogen atom, or form, together with the carbon atom to which they are attached, a group> C = 0, R? Represents a straight or branched chain alkyl radical, which contains 1 to 4 carbon atoms, optionally substituted by a cyclohexyl radical, R 'represents hydrogen or alkyl, X2 and Y2 each represent a hydrogen atom, or n together with the carbon atom to which a group is attached > C = 0, R. represents an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by hydroxy, alkoxy, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl, it being clear that, when R3 represents an alkyl radical substituted by a hydroxy radical , R3 can form with the carboxy radical in a lactone, R ':. represents hydrogen or alkyl, X represents an oxygen or sulfur atom, and R represents a hydrogen atom, or an optionally substituted alkyl radical, or an optionally substituted phenyl radical. These novel products have anti-cancer properties.