EP0808328A1 - Novel farnesyl transferase inhibitors, preparation thereof, and pharmaceutical compositions containing same - Google Patents

Novel farnesyl transferase inhibitors, preparation thereof, and pharmaceutical compositions containing same

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Publication number
EP0808328A1
EP0808328A1 EP96903061A EP96903061A EP0808328A1 EP 0808328 A1 EP0808328 A1 EP 0808328A1 EP 96903061 A EP96903061 A EP 96903061A EP 96903061 A EP96903061 A EP 96903061A EP 0808328 A1 EP0808328 A1 EP 0808328A1
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EP
European Patent Office
Prior art keywords
radical
hydrogen atom
carbon atoms
atom
alkyl
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EP96903061A
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German (de)
French (fr)
Inventor
François CLERC
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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Publication of EP0808328A1 publication Critical patent/EP0808328A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new farnesyl transferase inhibitors of general formula:
  • Inhibition of famesyl transferase and, therefore, famesylation 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 contains the motif "CAAX” or "Cys-Aaa] -Aaa2-Xaa” in which Aaa represents an aliphatic amino acid and Xaa represents any amino acid.
  • tetrapeptides with a CAAX sequence can inhibit famesylation of the ras protein.
  • peptides inhibitors of the famesyl transferase Cys-Aaa ⁇ -Aaa2-Xaa which are more particularly represented by the peptides Cys-Val-Leu- Ser, Cys-Val-Ile-Met and Cys-Val-Val-Met which manifest their inhibitory activity at concentrations close to 10 " ⁇ M or 10 -7 M.
  • Rj 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 a radical alkyl containing 1 to 6 carbon atoms optionally substituted by a phenyl radica, or radical of general formula
  • R2 represents a straight or branched alkyl radical containing 1 to 4 carbon atoms optionally substituted by a cyclohexyl radical
  • R'2 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms
  • R3 represents an alkyl radical containing straight or branched containing 1 to 4 carbon atoms optionally substituted by a hydroxy radical, alkoxy containing 1 to carbon atoms, mercapto, alkylthio containing 1 to 4 carbon atoms, alkylsul finyl containing 1 to 4 atoms carbon or alkylsulfonyl containing 1 to 4 carbon atoms, it being understood that, when R3 represents an alkyl radical substituted by a hydroxy radical, R3 can form with the carboxy radical in this a lactone, R'3 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
  • X represents an oxygen or sulfur atom
  • R represents a hydrogen atom or an alkyl radical optionally substituted by an alkoxy radical containing 1 to 4 carbon atoms, alkylthio containing 1 to carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms, alkylsulfonyl containing 1 to 4 carbon atoms, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, alkylamino containing 1 to 4 carbon atoms or dialkylamino each alkyl part of which contains 1 to 4 carbon atoms, or a phenyl radical optionally substituted by one or more identical or different atoms or radicals chosen from halogen atoms and alkyl, alkoxy, alkylthio or alkanoyl radicals containing 1 to 4 carbon atoms. More specifically,
  • R] represents a radical of formula YS-Aj- 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 optionally substituted ethylene or propylene radical by an amino radical,
  • R'2 represents a hydrogen atom or a methyl radical
  • R'3 represents a hydrogen atom or a methyl radical
  • X represents an oxygen atom
  • 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. More particularly still,
  • Rj represents a radical of formula YS-Aj- in which Y represents a hydrogen atom and Aj represents an ethylene or propylene radical optionally substituted by an amino radical, Xj and Y] each represent a hydrogen atom or form together with l carbon atom to which they are linked a group> CO,
  • R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical
  • R'2 represents a hydrogen atom
  • R3 represents a methyl or ethyl radical substituted by a hydrox methoxy, mercapto or methylthio radical
  • R'3 represents a hydrogen atom
  • R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms.
  • R ⁇ represents a 2-mercapto-ethyl or amino-1-mercapto-ethyl radical
  • X and Y each represent a hydrogen atom or together form the carbon atom to which they are linked a group> CO
  • R2 represents an isopropyl radical
  • R ' represents an atom of hydrogen
  • R3 represents a 2-methylthio-ethyl or 2-methylsulfinyl-ethyl radical
  • R'3 represents a hydrogen atom
  • R represents a hydrogen atom.
  • the present invention also relates to the stereoisomeric forms of products of general formula (I).
  • the amino acid residues represented by R 1 C (X 1 ) (Y ⁇ ), R2CH (NR ' 2 ) [C (X 2 ) (Y2)] and R 3 CH (NR' 3 ) CO-OH preferably have the configuration natural amino acids.
  • the present invention also relates to the mineral or organic salts as well as the esters of the products of general formula (I).
  • the new products of general formula (I) can be obtained by solid phase synthesis using a synthesis strategy "9-fluorenylmethoxycarbonyl (FMOC)".
  • FMOC 9-fluorenylmethoxycarbonyl
  • the thiol groups are protected by trityl or acetamidomethyl groups
  • the amino functions by Boc groups (t.butoxycarbonyl) and the acid functions in the form of t.butyl ester
  • the synthesis can be carried out on a resin confined in 3 cm3 solid phase extraction syringes made of high density polyethylene provided with teflon filters.
  • the syringes are mounted on a two-way teflon valve and closed with a disposable wing plug of high density polyethylene.
  • the syringes are shaken on a rotary device for hemolysis tubes.
  • the washing and filtration operations are carried out on a solid phase extraction workstation.
  • the syntheses are then carried out on 50 ⁇ moles of resin.
  • Amino acid couplings are carried out by treating the resin for 1 hour with 250 ⁇ mol of the amino acid suitably protected in the presence of 250 ⁇ mol of 2- (1H-benzotriazole-1-yl) -l, l, 3.3- tetramethyluronium, hexafluorophosphate (HBTU), 250 ⁇ moles of N-hydoxybenzotriazole and 750 ⁇ moles of diisopropylethylamine in 1.2 cm3 of an N-methylpyrrolidone-2 (NMP) / dimethylformamide mixture (1/1 by volume).
  • NMP N-methylpyrrolidone-2
  • the products are separated by treating the resin with 10 cm 3 of a trifluoroacetic acid-phenol-ethanedithiol-thioanisole-water mixture (40-3-1-2-2 by volume) 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 a trap at -90 ° C for 1.5 hours, the temperature of the evaporation being maintained at 50 ° C.
  • the final volume of the concentrate is approximately 1 cm3.
  • the product is then precipitated by adding 15 cm 3 of a mixture of methyl tert-butyl ether and ether of petroleum (2-1 by volume) then it is collected by centrifugation.
  • the pellet is then dissolved in 1 cm3 of trifluoroacetic acid, precipitated by addition of 15 cm3 of methyl-tert-butyl ether and then washed with 15 cm3 of methyl-tert-butyl ether.
  • the product is then dried under reduced pressure (3.5 kPa).
  • the product is finally purified by high performance liquid chromatography (HPLC) on a column C] 8 100 (250 x 10 mm, BioRad) eluted with an acetonitrile gradient containing 0.07% trifluoroacetic acid (by volume) in water containing 0.07% trifluoroacetic acid (by volume) at a flow rate of 6 cm3 / min and then lyophilized.
  • HPLC high performance liquid chromatography
  • the products obtained are characterized by their mass spectra (electrospray).
  • the introduction of the protective group FMOC on an amino acid e carried out by the action of the amino acid on the chloroformate of 9-fluorenylmethy (FMOC-chloride) in the presence of a base.
  • FMOC-Met-chlorotrityl resin can be obtained by reacting 250 ⁇ mol of chlorotritylchloride resin (Novabiochem®) with 1 mmol of FMOC-Methionine in 2 cm3 of dichloromethane and 0.5 cm3 of diisopropylethylamine for 30 minutes. After adding 2 cm 3 of methanol, the reaction is continued for a further 30 minutes. The resin is then washed with 4 cm3 of dichloromethane at times and then dried.
  • the famesyltransferase activity is determined by the amount of ( 3 H) famésy transferred from H) famesylpyrophosphate [( ⁇ H) FPP) to the p2 H-ras protein.
  • the standard reaction mixture is composed, for a final volume of 60 ⁇ l of 50 mM Tris-HCl, 5 mM MgCl2, 5 mM dithiotreitol, 0.2% octyl- ⁇ -D-glucopyranosid, p21 H-ras 200 picomoles, ( 3 H) FPP (at 61,000 dpm / picomole) 4.5 picomoles.
  • the reaction is initiated by the addition of approximately 5 ng of human famesyltransferas purified from cultures of THP1 cells. After incubation for 20 minutes at 37 ° C. in a microtitration plate containing 96 holes of 1 cm 3 per plate (Titer Plate®, Beckman), the reaction is stopped by adding 0.4 cm 3 of 0.1% SDS in methanol to 0 ° C. 0.4 cm 3 of trichloroacetic acid (TCA) 30% in methanol is then added to the mixture. The plates are left hanging for 1 hour in the ice. The precipitated content is then retained on a fiberglass membrane.
  • TCA trichloroacetic acid
  • the activity unit is defined by 1 picomole of ( 3 H) FPP transferred to p21 H-ras in 20 minutes.
  • the inhibition percentages are obtained by comparison of the tests with and without inhibitor after deduction of the blanks, the IC50 being measured from the inhibitions obtained with 9 different concentrations using the Enzfitter® or Graf it® software.
  • the new peptides of general formula (I) can be in the form of non-toxic and pharmaceutically acceptable salts.
  • These non-toxic salts include the salts with mineral acids (hydrochloric, sulfuric, hydrobromic, phosphoric, nitric) or with organic acids (acetic, propionic, succinic, maleic, hydroxymaleic, benzoic, fumaric, methanesulfonic, trifluoroacetic or oxalic acids) or with mineral bases (soda, potash, lithine, lime) or organic bases (tertiary amines such as triethylamine, piperidine, benzylamine) depending on the nature of the amino acids which constitute the peptide of general formula (I).
  • the new peptides according to the invention which inhibit famesyltransferase and famesylation of the Ras protein, are remarkable anticancer agents which act both in solid and liquid tumors.
  • the present invention also relates to pharmaceutical compositions which contain at least one peptide of general formula (I) in combination with a or more pharmaceutically acceptable diluents or adjuvants whether inert or physiologically active.
  • compositions can be administered orally, parenterally or rectally.
  • the compositions for oral administration include tablets, pills, powders or granules.
  • the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch.
  • these compositions can include substances other than diluents, for example a lubricant such as magnesium stearate.
  • As liquid compositions for oral administration can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil.
  • These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
  • compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate.
  • These compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, 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.
  • compositions according to the invention are particularly useful in human therapy in the treatment of cancers of various origins.
  • the doses depend on the desired effect, on the duration of the treatment and on the factors specific to the subject to be treated.
  • the doses are, in humans, between 0.1 and 20 mg / kg per day intraperitoneally.

Abstract

Novel farnesyl transferase inhibitors of general formula (I), preparation thereof, and pharmaceutical compositions containing same. In general formula (I), R1 is Y-S-A1- (where Y is a hydrogen atom, an amino acid residue, a fatty acid residue, an alkyl or alkoxycarbonyl radical, or a radical R4-S-, where R4 is a C1-6 alkyl radical optionally substituted by a phenyl radical, or a radical of general formula (II), wherein A1, X1, Y1, R2, R'2, X2, Y2, X, R3, R'3 and R are as defined below, and A1 is a C1-4 alkylene radical optionally α-substituted in the ⊃C(X1)(Y1) grouping by an amino, alkylamino, alkanoylamino or alkoxycarbonylamino radical); X1 and Y1 are each a hydrogen atom or, taken together with the carbon atom to which they are attached, a ⊃C=O grouping; R2 is a straight or branched C1-4 alkyl radical optionally substituted by a cyclohexyl radical; R'2 is hydrogen or alkyl; X2 and Y2 are each a hydrogen atom or, taken together with the carbon atom to which they are attached, a ⊃C=O grouping; R3 is a C1-4 alkyl radical optionally substituted by hydroxy, alkoxy, mercapto, alkylthio, alkylsulphinyl or alkylsulphonyl, with the proviso that, when R3 is an alkyl radical substituted by a hydroxy radical, R3 may form a lactone with the α-carboxy radical; R'3 is hydrogen or alkyl; X is an oxygen or sulphur atom; and R is a hydrogen atom or an optionally substituted alkyl radical or an optionally substituted phenyl radical. These novel products have anticancer properties.

Description

INHIBITEURS DE FARNESYL TRANSFERASE, LEUR PREPARATION ET LES COMPOSITIONSFARNESYL TRANSFERASE INHIBITORS, THEIR PREPARATION AND COMPOSITIONS
PHARMACEUTIQUES QUI LES CONTIENNENTPHARMACEUTICALS THAT CONTAIN THEM
La présente invention concerne de nouveaux inhibiteurs de farnésyl transférase de formule générale :The present invention relates to new farnesyl transferase inhibitors of general formula:
leur préparation et les compositions pharmaceutiques qui les contiennent. their preparation and the pharmaceutical compositions containing them.
L'inhibition de la famésyl transférase et, par conséquent, de la famesylation de la protéine ras, bloque la capacité de la protéine ras mutée à transformer les cellules normales en cellules cancéreuses.Inhibition of famesyl transferase and, therefore, famesylation of the ras protein, blocks the ability of the mutated ras protein to transform normal cells into cancer cells.
La séquence C-terminale du gène ras contient le motif "CAAX" ou "Cys-Aaa]-Aaa2-Xaa" dans lequel Aaa représente un aminoacide aliphatique et Xaa représente un aminoacide quelconque.The C-terminal sequence of the ras gene contains the motif "CAAX" or "Cys-Aaa] -Aaa2-Xaa" in which Aaa represents an aliphatic amino acid and Xaa represents any amino acid.
Il est connu que des tétrapeptides avec une séquence CAAX peuvent inhiber la famesylation de la protéine ras. Par exemple, dans la demande PCT WO 91/16340 et dans la demande EP 0 461 869 ont été décrits des peptides inhibiteurs de la famésyl transférase Cys-Aaaι-Aaa2-Xaa qui sont plus particulièrement représentés par les peptides Cys-Val-Leu-Ser, Cys-Val-Ile-Met et Cys-Val-Val-Met qui manifestent leur activité inhibitrice à des concentrations voisines de 10" ^M ou 10-7M.It is known that tetrapeptides with a CAAX sequence can inhibit famesylation of the ras protein. For example, in PCT application WO 91/16340 and in EP application 0 461 869 have been described peptides inhibitors of the famesyl transferase Cys-Aaaι-Aaa2-Xaa which are more particularly represented by the peptides Cys-Val-Leu- Ser, Cys-Val-Ile-Met and Cys-Val-Val-Met which manifest their inhibitory activity at concentrations close to 10 "^ M or 10 -7 M.
Il a maintenant été trouvé, et c'est ce qui fait l'objet de la présente invention, que les peptides de formule générale (I) manifestent leur activité inhibitrice (IC50) à des concentrations de l'ordre de 10'^M.It has now been found, and this is the subject of the present invention, that the peptides of general formula (I) manifest their inhibitory activity (IC50) at concentrations of the order of 10 '^ M.
Dans la formule générale (I), Rj représente un radical de formule générale Y-S-A}- dans lequel Y représente un atome d'hydrogène, ou un reste d'aminoacide ou un reste d'acide gras ou un radical alkyle ou alkoxycarbonyle, ou un radical R4-S- dans lequel R4 représente un radical alkyle contenant 1 à 6 atomes de carbone éventuellement substitué par un radica phényle, ou radical de formule généraleIn the general formula (I), Rj 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 a radical alkyl containing 1 to 6 carbon atoms optionally substituted by a phenyl radica, or radical of general formula
dans laquelle Aj, Xi , Yi , R2. R'2> ^2> ^2» ^> ^3» ^ 3 et ^ sont définis comm ci-après, et Aj représente un radical alcoylène droit ou ramifié contenant 1 à atomes de carbone éventuellement substitué en α du groupement >C(Xι )(Yι) par u radical amino, alkylamino contenant 1 à 4 atomes de carbone, alcanoylamin contenant 1 à 4 atomes de carbone ou alkoxycarbonylamino dont la partie alkyl contient 1 à 4 atomes de carbone, Xj et Yj représentent chacun un atome d'hydrogène ou forment ensemble ave l'atome de carbone auquel ils sont liés un groupement >C=O, in which Aj, Xi, Yi, R2. R'2> ^ 2> ^ 2 »^> ^ 3» ^ 3 and ^ are defined as below, and Aj represents a straight or branched alkylene radical containing 1 to carbon atoms optionally substituted at α of the group> C ( Xι) (Yι) by u amino radical, alkylamino containing 1 to 4 carbon atoms, alkanoylamin containing 1 to 4 carbon atoms or alkoxycarbonylamino of which the alkyl part contains 1 to 4 carbon atoms, Xj and Yj each represent an atom of hydrogen or together form with the carbon atom to which they are linked a group> C = O,
R2 représente un radical alkyle droit ou ramifié contenant 1 à 4 atomes de carbon éventuellement substitué par un radical cyclohexyle, R'2 représente un atome d'hydrogène ou un radical alkyle droit ou ramifié contenant 1 à 6 atomes de carbone,R2 represents a straight or branched alkyl radical containing 1 to 4 carbon atoms optionally substituted by a cyclohexyl radical, R'2 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble ave l'atome de carbone auquel ils sont liés un groupement >C=O,X2 and Y2 each represent a hydrogen atom or together form, with the carbon atom to which they are linked, a group> C = O,
R3 représente un radical alkyle contenant droit ou ramifié contenant 1 à 4 atomes d carbone éventuellement substitué par un radical hydroxy, alkoxy contenant 1 à atomes de carbone, mercapto, alkylthio contenant 1 à 4 atomes de carbone, alkylsul finyle contenant 1 à 4 atomes de carbone ou alkylsulfonyle contenant 1 à 4 atomes d carbone, étant entendu que, lorsque R3 représente un radical alkyle substitué par u radical hydroxy, R3 peut former avec le radical carboxy en ce une lactone, R'3 représente un atome d'hydrogène ou un radical alkyle droit ou ramifié contenant 1 à 6 atomes de carbone,R3 represents an alkyl radical containing straight or branched containing 1 to 4 carbon atoms optionally substituted by a hydroxy radical, alkoxy containing 1 to carbon atoms, mercapto, alkylthio containing 1 to 4 carbon atoms, alkylsul finyl containing 1 to 4 atoms carbon or alkylsulfonyl containing 1 to 4 carbon atoms, it being understood that, when R3 represents an alkyl radical substituted by a hydroxy radical, R3 can form with the carboxy radical in this a lactone, R'3 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
X représente un atome d'oxygène ou de soufre, etX represents an oxygen or sulfur atom, and
R représente un atome d'hydrogène ou un radical alkyle éventuellement substitué pa un radical alkoxy contenant 1 à 4 atomes de carbone, alkylthio contenant 1 à atomes de carbone, alkylsulfinyle contenant 1 à 4 atomes de carbone, alkylsulfonyle contenant 1 à 4 atomes de carbone, phényle, phénoxy, phenylthio, phénylsulfinyle, phénylsulfonyle, alkylamino contenant 1 à 4 atomes de carbone ou dialkylamino dont chaque partie alkyle contient 1 à 4 atomes de carbone, ou un radical phényle éventuellement substitué par un ou plusieurs atomes ou radicaux, identiques ou différents choisis parmi les atomes d'halogène et les radicaux alkyles, alkoxy, alkylthio ou alcanoyle contenant 1 à 4 atomes de carbone. Plus particulièrement,R represents a hydrogen atom or an alkyl radical optionally substituted by an alkoxy radical containing 1 to 4 carbon atoms, alkylthio containing 1 to carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms, alkylsulfonyl containing 1 to 4 carbon atoms, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, alkylamino containing 1 to 4 carbon atoms or dialkylamino each alkyl part of which contains 1 to 4 carbon atoms, or a phenyl radical optionally substituted by one or more identical or different atoms or radicals chosen from halogen atoms and alkyl, alkoxy, alkylthio or alkanoyl radicals containing 1 to 4 carbon atoms. More specifically,
R] représente un radical de formule Y-S-Aj- dans lequel Y représente un atome d'hydrogène ou un reste lysine ou un reste d'acide gras contenant jusqu'à 20 atomes de carbone et A] représente un radical éthylène ou propylène éventuellement substitué par un radical amino,R] represents a radical of formula YS-Aj- 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 optionally substituted ethylene or propylene radical by an amino radical,
X] et Y] représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O, R2 représente un radical isopropyle, méthyl-1 propyle, tert-butyle ou cyclohexyl- méthyle,X] and Y] each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C = O, R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical ,
R'2 représente un atome d'hydrogène ou un radical méthyle,R'2 represents a hydrogen atom or a methyl radical,
X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O, R3 représente un radical méthyle ou éthyle substitué par un radical hydroxy, méthoxy, mercapto, méthylthio, méthylsulfinyle ou méthylsulfonyle,X2 and Y2 each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C = O, R3 represents a methyl or ethyl radical substituted by a hydroxy, methoxy, mercapto, methylthio, methylsulfinyl radical or methylsulfonyl,
R'3 représente un atome d'hydrogène ou un radical méthyle,R'3 represents a hydrogen atom or a methyl radical,
X représente un atome d'oxygène, etX represents an oxygen atom, and
R représente un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical alcoxy, ou un radical phényle. Plus particulièrement encore,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. More particularly still,
Rj représente un radical de formule Y-S-Aj- dans lequel Y représente un atome d'hydrogène et Aj représente un radical éthylène ou propylène éventuellement substitué par un radical amino, Xj et Y] représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >CO,Rj represents a radical of formula YS-Aj- in which Y represents a hydrogen atom and Aj represents an ethylene or propylene radical optionally substituted by an amino radical, Xj and Y] each represent a hydrogen atom or form together with l carbon atom to which they are linked a group> CO,
R2 représente un radical isopropyle, méthyl-1 propyle, tert-butyle ou cyclohexyl- méthyle,R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical,
R'2 représente un atome d'hydrogène, X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble ave l'atome de carbone auquel ils sont liés un groupement >C=O,R'2 represents a hydrogen atom, X2 and Y2 each represent a hydrogen atom or together form, with the carbon atom to which they are linked, a group> C = O,
R3 représente un radical méthyle ou éthyle substitué par un radical hydrox méthoxy, mercapto ou méthylthio, R'3 représente un atome d'hydrogène, etR3 represents a methyl or ethyl radical substituted by a hydrox methoxy, mercapto or methylthio radical, R'3 represents a hydrogen atom, and
R représente un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes d carbone.R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms.
Tout particulièrement intéressants sont les produits de formule générale (I dans laquelle R\ représente un radical mercapto-2 éthyle ou amino- 1 mercapto- éthyle, X et Y] représentent chacun un atome d'hydrogène ou forment ensembl avec l'atome de carbone auquel ils sont liés un groupement >CO, R2 représente u radical isopropyle, X2 et Y2 représentent chacun un atome d'hydrogène ou formen ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O, R' représente un atome d'hydrogène, R3 représente un radical méthylthio-2 éthyle o méthylsulfinyle-2 éthyle, R'3 représente un atome d'hydrogène et R représente u atome d'hydrogène.Very particularly interesting are the products of general formula (I in which R \ represents a 2-mercapto-ethyl or amino-1-mercapto-ethyl radical, X and Y] each represent a hydrogen atom or together form the carbon atom to which they are linked a group> CO, R2 represents an isopropyl radical, X2 and Y2 each represent a hydrogen atom or formed together with the carbon atom to which they are linked a group> C = O, R 'represents an atom of hydrogen, R3 represents a 2-methylthio-ethyl or 2-methylsulfinyl-ethyl radical, R'3 represents a hydrogen atom and R represents a hydrogen atom.
La présente invention concerne également les formes stéréoisomères de produits de formule générale (I). Les restes des aminoacides représentés pa R1C(X1)(Yι), R2CH(NR'2)[C(X2)(Y2)] et R3CH(NR'3)CO-OH ont de préférence l configuration des aminoacides naturels.The present invention also relates to the stereoisomeric forms of products of general formula (I). The amino acid residues represented by R 1 C (X 1 ) (Yι), R2CH (NR ' 2 ) [C (X 2 ) (Y2)] and R 3 CH (NR' 3 ) CO-OH preferably have the configuration natural amino acids.
La présente invention concerne également les sels minéraux ou organique ainsi que les esters des produits de formule générale (I).The present invention also relates to the mineral or organic salts as well as the esters of the products of general formula (I).
Selon l'invention, les nouveaux produits de formule générale (I) peuvent êtr obtenus par synthèse en phase solide en utilisant une stratégie de synthès "9-fluorénylméthoxycarbonyl (FMOC)". Dans ce cas, les groupements thiols son protégés par des groupements trityl ou acétamidométhyl, les fonctions aminés par de groupements Boc (t.butoxycarbonyl) et les fonctions acides sous forme d'este t.butylique, les fonctions alcool par des groupements t.butyl et les fonctions amide e imidazole par des groupements trityl. La synthèse peut être réalisée sur une résin confinée dans des seringues d'extraction en phase solide de 3 cm3 en polyéthylen haute densité munies de filtres en teflon. Les seringues sont montées sur une vanne deux voies en teflon et fermées par un bouchon à ailettes à usage unique e polyéthylene haute densité. L'agitation des seringues est réalisée sur un apparei rotatif pour tubes à hémolyse. Les opérations de lavage et de filtration sont conduite sur une station de travail d'extraction en phase solide. Les synthèses sont alors réalisées sur 50 μmoles de résine. Les couplages des acides aminés sont réalisés en traitant pendant 1 heure la résine par 250 μmoles de l'acide aminé convenablement protégé en présence de 250 μmoles de 2-(lH- benzotriazole-l-yl)-l,l,3,3-tétraméthyluronium, hexafluorophosphate (HBTU), 250 μmoles de N-hydoxybenzotriazole et 750 μmoles de diisopropyléthylamine dans 1,2 cm3 d'un mélange N-méthylpyrrolidone-2 (NMP)/diméthylformamide (1/1 en volume). La déprotection du groupement FMOC est réalisée par 3 traitements successifs de la résine pendant 2 fois 1 minute puis 20 minutes par 2 cm3 de pipéridine en solution à 2 % (v/v) dans la NMP. Par exemple, la Cys-(NMe)Val-[cis-3-phényl-DL-prolyl]-Met peut être préparée de la manière suivante :According to the invention, the new products of general formula (I) can be obtained by solid phase synthesis using a synthesis strategy "9-fluorenylmethoxycarbonyl (FMOC)". In this case, the thiol groups are protected by trityl or acetamidomethyl groups, the amino functions by Boc groups (t.butoxycarbonyl) and the acid functions in the form of t.butyl ester, the alcohol functions by t.butyl groups. and the amide and imidazole functions by trityl groups. The synthesis can be carried out on a resin confined in 3 cm3 solid phase extraction syringes made of high density polyethylene provided with teflon filters. The syringes are mounted on a two-way teflon valve and closed with a disposable wing plug of high density polyethylene. The syringes are shaken on a rotary device for hemolysis tubes. The washing and filtration operations are carried out on a solid phase extraction workstation. The syntheses are then carried out on 50 μmoles of resin. Amino acid couplings are carried out by treating the resin for 1 hour with 250 μmol of the amino acid suitably protected in the presence of 250 μmol of 2- (1H-benzotriazole-1-yl) -l, l, 3.3- tetramethyluronium, hexafluorophosphate (HBTU), 250 μmoles of N-hydoxybenzotriazole and 750 μmoles of diisopropylethylamine in 1.2 cm3 of an N-methylpyrrolidone-2 (NMP) / dimethylformamide mixture (1/1 by volume). Deprotection of the FMOC group is carried out by 3 successive treatments of the resin for 2 times 1 minute then 20 minutes with 2 cm 3 of piperidine in 2% solution (v / v) in NMP. For example, Cys- (NMe) Val- [cis-3-phenyl-DL-prolyl] -Met can be prepared as follows:
On soumet successivement 50 μmoles de résine Fmoc-Met-chlorotrityl aux traitements suivants :50 μmoles of Fmoc-Met-chlorotrityl resin are successively subjected to the following treatments:
- déprotection du groupement FMOC, - lavage par 5 fois 2 cm3 de NMP,- deprotection of the FMOC group, - washing with 5 times 2 cm3 of NMP,
- couplage de la FMOC-cis-3-phényl-DL-proline,- coupling of FMOC-cis-3-phenyl-DL-proline,
- lavage par 5 fois 2 cm3 de NMP,- washing with 5 times 2 cm3 of NMP,
- déprotection du groupement FMOC,- deprotection of the FMOC group,
- lavage par 5 fois 2 cm3 de NMP, - couplage de la FMOC-N-méthylvaline,- washing with 5 times 2 cm3 of NMP, - coupling of FMOC-N-methylvaline,
- lavage par 5 fois 2 cm3 de NMP,- washing with 5 times 2 cm3 of NMP,
- déprotection du groupement FMOC,- deprotection of the FMOC group,
- lavage par 5 fois 2 cm3 de NMP,- washing with 5 times 2 cm3 of NMP,
- couplage de la FMOC-cystéine(S-trityl), - lavage par 5 fois 2 cm3 de NMP,- coupling of FMOC-cysteine (S-trityl), - washing with 5 times 2 cm3 of NMP,
- déprotection du groupement FMOC,- deprotection of the FMOC group,
- lavage par 5 fois 2 cm3 de NMP.- washing with 5 times 2 cm3 of NMP.
La synthèse terminée, les produits sont séparés par traitement de la résine par 10 cm3 d'un mélange acide trifluoroacétique-phénol-éthanedithiol-thioanisole-eau (40-3-1-2-2 en volumes) pendant 1 heure 30 minutes. La résine est ensuite éliminée par filtration. Le filtrat est concentré sous pression réduite au moyen d'un évaporateur centrifuge (RC10-10 Jouan) équipé d'une pompe à palettes et d'un piège à -90°C pendant 1,5 heures, la température de la chambre d'évaporation étant maintenue à 50°C. Le volume final du concentrât est d'environ 1 cm3. Le produit est ensuite précipité par addition de 15 cm3 d'un mélange de méthyl-tert-butyléther et d'éther de pétrole (2-1 en volumes) puis il est recueilli par centrifugation. Le culot est ensuit solubilisé dans 1 cm3 d'acide trifluoroacétique, précipité par addition de 15 cm3 d méthyl-tert-butyléther puis lavé par 15 cm3 de méthyl-tert-butyléther. Le produit e ensuite séché sous pression réduite (3,5 kPa). Le produit est enfin purifié pa chromatographie liquide à haute performance (HPLC) sur une colonne C] 8 100 (250 x 10 mm, BioRad) éluée par un gradient d'acétonitrile contenant 0,07 % d'acid trifluoroacétique (en volumes) dans l'eau contenant 0,07 % d'acide trifluoroacétiqu (en volumes) à un débit de 6 cm3/min puis lyophilisé. Les produits obtenus son caractérisés par leurs spectres de masse (electrospray). L'introduction du groupement protecteur FMOC sur un aminoacide e effectuée par action de l'aminoacide sur le chloroformiate de 9-fluorénylméthy (FMOC-chlorure) en présence d'une base.Once the synthesis is complete, the products are separated by treating the resin with 10 cm 3 of a trifluoroacetic acid-phenol-ethanedithiol-thioanisole-water mixture (40-3-1-2-2 by volume) 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 a trap at -90 ° C for 1.5 hours, the temperature of the evaporation being maintained at 50 ° C. The final volume of the concentrate is approximately 1 cm3. The product is then precipitated by adding 15 cm 3 of a mixture of methyl tert-butyl ether and ether of petroleum (2-1 by volume) then it is collected by centrifugation. The pellet is then dissolved in 1 cm3 of trifluoroacetic acid, precipitated by addition of 15 cm3 of methyl-tert-butyl ether and then washed with 15 cm3 of methyl-tert-butyl ether. The product is then dried under reduced pressure (3.5 kPa). The product is finally purified by high performance liquid chromatography (HPLC) on a column C] 8 100 (250 x 10 mm, BioRad) eluted with an acetonitrile gradient containing 0.07% trifluoroacetic acid (by volume) in water containing 0.07% trifluoroacetic acid (by volume) at a flow rate of 6 cm3 / min and then lyophilized. The products obtained are characterized by their mass spectra (electrospray). The introduction of the protective group FMOC on an amino acid e carried out by the action of the amino acid on the chloroformate of 9-fluorenylmethy (FMOC-chloride) in the presence of a base.
La résine FMOC-Met-chlorotrityl peut être obtenue par réaction d 250 μmoles de résine chlorotritylchlorure (Novabiochem®) avec 1 mmole d FMOC-Méthionine dans 2 cm3 de dichlorométhane et 0,5 cm3 d diisopropyléthylamine pendant 30 minutes. Après addition de 2 cm3 de méthanol, l réaction est poursuivie pendant encore 30 minutes. La résine est ensuite lavée par fois 4 cm3 de dichlorométhane puis séchée.FMOC-Met-chlorotrityl resin can be obtained by reacting 250 μmol of chlorotritylchloride resin (Novabiochem®) with 1 mmol of FMOC-Methionine in 2 cm3 of dichloromethane and 0.5 cm3 of diisopropylethylamine for 30 minutes. After adding 2 cm 3 of methanol, the reaction is continued for a further 30 minutes. The resin is then washed with 4 cm3 of dichloromethane at times and then dried.
Les cis- et trans-phénylprolines, sous forme racémique, peuvent êtr obtenues dans les conditions décrites par R. Sarges et J. R. Tretter, J. Org. Chem., 39 1710 (1974).The cis- and trans-phenylprolines, in racemic form, can be obtained under the conditions described by R. Sarges and J. R. Tretter, J. Org. Chem., 39 1710 (1974).
L'activité inhibitrice de la famésyltransférase et de la famesylation de l protéine Ras peut être mise en évidence dans le test suivant :The inhibitory activity of famesyltransferase and famesylation of the Ras protein can be demonstrated in the following test:
L'activité famésyltransférase est déterminée par la quantité de (3H) famésy transférée à partir du H) famésylpyrophosphate [(^H) FPP) sur la protéine p2 H-ras. Le mélange réactionnel standard est composé, pour un volume final de 60 μl de Tris-HCl 50mM, MgCl2 5mM, dithiotréitol 5 mM, octyl-β-D-glucopyranosid 0,2 %, p21 H-ras 200 picomoles, (3H) FPP (à 61000 dpm/picomole) 4,5 picomoles.The famesyltransferase activity is determined by the amount of ( 3 H) famésy transferred from H) famesylpyrophosphate [(^ H) FPP) to the p2 H-ras protein. The standard reaction mixture is composed, for a final volume of 60 μl of 50 mM Tris-HCl, 5 mM MgCl2, 5 mM dithiotreitol, 0.2% octyl-β-D-glucopyranosid, p21 H-ras 200 picomoles, ( 3 H) FPP (at 61,000 dpm / picomole) 4.5 picomoles.
La réaction est initiée par addition d'environ 5 ng de famésyltransféras humaine purifiée à partir de cultures de cellules THPl . Après incubation pendan 20 minutes à 37°C en plaque de microtitration contenant 96 trous de 1 cm3 par plaqu (Titer Plate®, Beckman), la réaction est stoppée par addition de 0,4 cm3 de SDS 0,1 % dans le méthanol à 0°C. Le mélange est ensuite additionné de 0,4 cm3 d'acide trichloroacétique (TCA) à 30 % dans le méthanol. Les plaques sont laissées pendan 1 heure dans la glace. Le contenu précipité est alors retenu sur membrane en fibre de verre Filtermat®, Pharmacia) avec l'unité de filtration (Combi Cell Harvester®, Skatron) et rincé avec de l'acide trichloroacétique à 6 % dans l'eau distillée. Les membranes sont séchées au four à micro-ondes puis imprégnées de scintillant par fusion sous air chaud de Meltilex® (Pharmacia) et enfin comptées en cpm dans un compteur β-Plate® (LKB). Chaque essai est répété 3 fois.The reaction is initiated by the addition of approximately 5 ng of human famesyltransferas purified from cultures of THP1 cells. After incubation for 20 minutes at 37 ° C. in a microtitration plate containing 96 holes of 1 cm 3 per plate (Titer Plate®, Beckman), the reaction is stopped by adding 0.4 cm 3 of 0.1% SDS in methanol to 0 ° C. 0.4 cm 3 of trichloroacetic acid (TCA) 30% in methanol is then added to the mixture. The plates are left hanging for 1 hour in the ice. The precipitated content is then retained on a fiberglass membrane. Filtermat® glass, Pharmacia) with the filtration unit (Combi Cell Harvester®, Skatron) and rinsed with 6% trichloroacetic acid in distilled water. The membranes are dried in the microwave oven then impregnated with scintillant by melting under hot air with Meltilex® (Pharmacia) and finally counted in cpm in a β-Plate® counter (LKB). Each test is repeated 3 times.
L'unité d'activité est définie par 1 picomole de (3H) FPP transférée sur p21 H-ras en 20 minutes.The activity unit is defined by 1 picomole of ( 3 H) FPP transferred to p21 H-ras in 20 minutes.
Les pourcentages d'inhibition sont obtenus par comparaison des essais avec et sans inhibiteur après déduction des blancs, les IC50 étant mesurées à partir des inhibitions obtenues avec 9 concentrations différentes en utilisant les logiciels Enzfitter® ou Graf it®.The inhibition percentages are obtained by comparison of the tests with and without inhibitor after deduction of the blanks, the IC50 being measured from the inhibitions obtained with 9 different concentrations using the Enzfitter® or Graf it® software.
Les résultats obtenus sont rassemblés dans le tableau I.The results obtained are collated in Table I.
TABLEAU ITABLE I
ActivitéActivity
Produit inhibitriceInhibitory product
IC50IC50
Cys-(N-Me)Val-[cis-3-phényl-DL-prolyl]-Met 1,55 x lO"8 MCys- (N-Me) Val- [cis-3-phenyl-DL-prolyl] -Met 1.55 x 10 "8 M
Cys-(N-Me)Val-[trans-3-phényl-DL-prolylJ-Met 9,2 x 10"7 MCys- (N-Me) Val- [trans-3-phenyl-DL-prolylJ-Met 9.2 x 10 "7 M
Les nouveaux peptides de formule générale (I) peuvent se présenter sous forme de sels non toxiques et pharmaceutiquement acceptables. Ces sels non toxiques comprennent les sels avec les acides minéraux (acides chlorhydrique, sulfurique, bromhydrique, phosphorique, nitrique) ou avec les acides organiques (acides acétique, propionique, succinique, maléique, hydroxymaléique, benzoïque, fumarique, méthanesulfonique, trifluoroacétique ou oxalique) ou avec les bases minérales (soude, potasse, lithine, chaux) ou organiques (aminés tertiaires comme la triéthylamine, la pipéridine, la benzylamine) selon la nature des aminoacides qui constituent le peptide de formule générale (I).The new peptides of general formula (I) can be in the form of non-toxic and pharmaceutically acceptable salts. These non-toxic salts include the salts with mineral acids (hydrochloric, sulfuric, hydrobromic, phosphoric, nitric) or with organic acids (acetic, propionic, succinic, maleic, hydroxymaleic, benzoic, fumaric, methanesulfonic, trifluoroacetic or oxalic acids) or with mineral bases (soda, potash, lithine, lime) or organic bases (tertiary amines such as triethylamine, piperidine, benzylamine) depending on the nature of the amino acids which constitute the peptide of general formula (I).
Les nouveaux peptides selon l'invention, qui inhibent la famésyltransférase et la famesylation de la protéine Ras, sont des agents anticancéreux remarquables qui agissent tant au niveau des tumeurs solides que liquides.The new peptides according to the invention, which inhibit famesyltransferase and famesylation of the Ras protein, are remarkable anticancer agents which act both in solid and liquid tumors.
La présente invention concerne également les compositions pharmaceutiques qui contiennent au moins un peptide de formule générale (I) en association avec un ou plusieurs diluants ou adjuvants pharmaceutiquement acceptables qu'ils soient inertes ou physiologiquement actifs.The present invention also relates to pharmaceutical compositions which contain at least one peptide of general formula (I) in combination with a or more pharmaceutically acceptable diluents or adjuvants whether inert or physiologically active.
Ces compositions peuvent être administrées par voie orale, parentérale ou rectale. Les compositions pour administration orale comprennent des comprimés, des pilules, des poudres ou des granulés. Dans ces compositions le produit actif selon l'invention est mélangé à un ou plusieurs diluants inertes tels que saccharose, lactose ou amidon. Ces compositions peuvent comprendre des substances autres que les diluants, par exemple un lubrifiant tel que le stéarate de magnésium. Comme compositions liquides pour administration orale peuvent être utilisées des émulsions pharmaceutiquement acceptables, des solutions, des suspensions, des sirops, des élixirs contenant des diluants inertes tel que l'eau ou l'huile de paraffine. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple des produits mouillants, édulcorants ou aromatisants.These compositions can be administered orally, parenterally or rectally. The compositions for oral administration include tablets, pills, powders or granules. In these compositions, the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions can include substances other than diluents, for example a lubricant such as magnesium stearate. As liquid compositions for oral administration can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
Les compositions selon l'invention pour administration parentérale peuvent être des solutions stériles aqueuses ou non aqueuses, des suspensions ou des émulsions. Comme solvant ou véhicule, on peut employer le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive ou des esters organiques injectables par exemple l'oléate d'éthyle. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, émulsifiants et dispersants. La stérilisation peut se faire de plusieurs façons, par exemple à l'aide d'un filtre bactériologique, en incorporant à la composition des agents stérilisants ou par chauffage. Elles peuvent être également préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans de l'eau stérile ou tout autre milieu stérile injectable.The compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As 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 can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, 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.
Les compositions pour administration rectale sont des suppositoires qui peuvent contenir, outre le produit actif, des excipients tels que le beurre de cacao.The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter.
Les compositions selon l'invention sont particulièrement utiles en thérapeutique humaine dans le traitement de cancers d'origines diverses.The compositions according to the invention are particularly useful in human therapy in the treatment of cancers of various origins.
En thérapeutique humaine, les doses dépendent de l'effet recherché, de la durée du traitement et des facteurs propres au sujet à traiter.In human therapy, the doses depend on the desired effect, on the duration of the treatment and on the factors specific to the subject to be treated.
Généralement, les doses sont comprises, chez l'homme, entre 0,1 et 20 mg/kg par jour par voie intra-péritonéale. Generally, the doses are, in humans, between 0.1 and 20 mg / kg per day intraperitoneally.

Claims

REVENDICATIONS
1 - Nouveaux peptides de formule générale :1 - New peptides of general formula:
dans laquelle : in which :
Rj représente un radical de formule générale Y-S-Aj- dans lequel Y représente un atome d'hydrogène, ou un reste d'aminoacide ou un reste d'acide gras ou un radical alkyle ou alkoxycarbonyle, ou un radical R4-S- dans lequel R4 représente un radical alkyle contenant 1 à 6 atomes de carbone éventuellement substitué par un radical phényle, ou radical de formule généraleRj represents a radical of general formula YS-Aj- 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 R4-S- radical in which R4 represents an alkyl radical containing 1 to 6 carbon atoms optionally substituted by a phenyl radical, or radical of general formula
dans laquelle Ai , Xj , Yj , R2, '2. ^2- ^2< X> ^3- ^ 3 et R sont définis corne ci-après, et Ai représente un radical alcoylène droit ou ramifié contenant 1 à 4 atomes de carbone éventuellement substitué en α du groupement >C(Xj)(Yι) par un radical amino, alkylamino contenant 1 à 4 atomes de carbone, alcanoylamino contenant 1 à 4 atomes de carbone ou alkoxycarbonylamino dont la partie alkyle contient 1 à 4 atomes de carbone, in which Ai, Xj, Yj, R2, '2. ^ 2- ^ 2 <X> ^ 3- ^ 3 and R are defined as follows, and Ai represents a straight or branched alkylene radical containing 1 to 4 carbon atoms optionally substituted at α of the group> C (Xj) ( Yι) by an amino radical, alkylamino containing 1 to 4 carbon atoms, alkanoylamino containing 1 to 4 carbon atoms or alkoxycarbonylamino in which the alkyl part contains 1 to 4 carbon atoms,
Xi et Yi représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O, R2 représente un radical alkyle droit ou ramifié contenant 1 à 4 atomes de carbone éventuellement substitué par un radical cyclohexyle, R'2 représente un atome d'hydrogène ou un radical alkyle droit ou ramifié contenant 1 à 6 atomes de carbone,Xi and Yi each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C = O, R2 represents a straight or branched alkyl radical containing 1 to 4 carbon atoms optionally substituted by a radical cyclohexyl, R'2 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble ave l'atome de carbone auquel ils sont liés un groupement >C=O, R3 représente un radical alkyle contenant droit ou ramifié contenant 1 à 4 atomes d carbone éventuellement substitué par un radical hydroxy, alkoxy contenant 1 à atomes de carbone, mercapto, alkylthio contenant 1 à 4 atomes de carbone, alkylsul finyle contenant 1 à 4 atomes de carbone ou alkylsulfonyle contenant 1 à 4 atomes d carbone, étant entendu que, lorsque R3 représente un radical alkyle substitué par u radical hydroxy, R3 peut former avec le radical carboxy en a une lactone,X2 and Y2 each represent a hydrogen atom or together form, with the carbon atom to which they are linked, a group> C = O, R3 represents an alkyl radical containing straight or branched containing 1 to 4 carbon atoms optionally substituted by a hydroxy radical, alkoxy containing 1 to carbon atoms, mercapto, alkylthio containing 1 to 4 carbon atoms, alkylsul finyl containing 1 to 4 carbon atoms or alkylsulfonyl containing 1 to 4 carbon atoms, it being understood that when R3 represents a radical alkyl substituted by a hydroxy radical, R3 can form, with the carboxy radical, to a lactone,
R'3 représente un atome d'hydrogène ou un radical alkyle droit ou ramifié contenant 1 à 6 atomes de carbone,R'3 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
X représente un atome d'oxygène ou de soufre, etX represents an oxygen or sulfur atom, and
R représente un atome d'hydrogène ou un radical alkyle éventuellement substitué par un radical alkoxy contenant 1 à 4 atomes de carbone, alkylthio contenant 1 à 4 atomes de carbone, alkylsulfinyle contenant 1 à 4 atomes de carbone, alkylsulfonyle contenant 1 à 4 atomes de carbone, phényle, phénoxy, phenylthio, phénylsulfinyle, phénylsulfonyle, alkylamino contenant 1 à 4 atomes de carbone ou dialkylamino dont chaque partie alkyle contient 1 à A atomes de carbone, ou un radical phényle éventuellement substitué par un ou plusieurs atomes ou radicaux, identiques ou différents choisis parmi les atomes d'halogène et les radicaux alkyles, alkoxy, alkylthio ou alcanoyle contenant 1 à 4 atomes de carbone.R represents a hydrogen atom or an alkyl radical optionally substituted by an alkoxy radical containing 1 to 4 carbon atoms, alkylthio containing 1 to 4 carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms, alkylsulfonyl containing 1 to 4 atoms carbon, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, alkylamino containing 1 to 4 carbon atoms or dialkylamino each alkyl part of which contains 1 to A carbon atoms, or a phenyl radical optionally substituted by one or more atoms or radicals, identical or different ones chosen from halogen atoms and alkyl, alkoxy, alkylthio or alkanoyl radicals containing 1 to 4 carbon atoms.
2 - Nouveaux peptides selon la revendication 1 pour lesquels2 - New peptides according to claim 1 for which
R représente un radical de formule Y-S-Aj- dans lequel Y représente un atome d'hydrogène ou un reste lysine ou un reste d'acide gras contenant jusqu'à 20 atomes de carbone et Aj représente un radical éthylène ou propylène éventuellement substitué par un radical amino,R represents a radical of formula YS-Aj- in which Y represents a hydrogen atom or a lysine residue or a fatty acid residue containing up to 20 carbon atoms and Aj represents an ethylene or propylene radical optionally substituted by a amino radical,
Xi et Yj représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C≈O, R2 représente un radical isopropyle, méthyl-1 propyle, tert-butyle ou cyclohexyl- méthyle,Xi and Yj each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C≈O, R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical,
R'2 représente un atome d'hydrogène ou un radical méthyle,R'2 represents a hydrogen atom or a methyl radical,
X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O, R3 représente un radical méthyle ou éthyle substitué par un radical , méthoxy, mercapto, méthylthio, méthylsulfinyle ou méthylsulfonyle, R'3 représente un atome d'hydrogène ou un radical méthyle, X représente un atome d'oxygène, et R représente un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical alcoxy, ou un radical phényle.X2 and Y2 each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C = O, R3 represents a methyl or ethyl radical substituted by a radical , methoxy, mercapto, methylthio, methylsulfinyl or methylsulfonyl, 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 atoms carbon optionally substituted by an alkoxy radical, or a phenyl radical.
3 - Nouveaux peptides selon la revendication 1 pour lesquels3 - New peptides according to claim 1 for which
Rj représente un radical de formule Y-S-Aj- dans lequel Y représente un atome d'hydrogène et Aj représente un radical éthylène ou propylène éventuellement substitué par un radical amino,Rj represents a radical of formula Y-S-Aj- in which Y represents a hydrogen atom and Aj represents an ethylene or propylene radical optionally substituted by an amino radical,
Xj et Yj représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >CO,Xj and Yj each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> CO,
R2 représente un radical isopropyle, méthyl-1 propyle, tert-butyle ou cyclohexyl- méthyle, R'2 représente un atome d'hydrogène,R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical, R'2 represents a hydrogen atom,
X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O,X2 and Y2 each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C = O,
R3 représente un radical méthyle ou éthyle substitué par un radical hydroxy, méthoxy, mercapto ou méthylthio, R'3 représente un atome d'hydrogène, etR3 represents a methyl or ethyl radical substituted by a hydroxy, methoxy, mercapto or methylthio radical, R'3 represents a hydrogen atom, and
R représente un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes de carbone.R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms.
4 - Nouveaux peptides selon la revendication 1 pour lesquels Rj représente un radical mercapto-2 éthyle ou amino- 1 mercapto-2 éthyle, Xi et Y] représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >CO, R2 représente un radical isopropyle, X2 et Y2 représentent chacun un atome d'hydrogène ou forment ensemble avec l'atome de carbone auquel ils sont liés un groupement >C=O, R'2 représente un atome d'hydrogène, R3 représente un radical méthylthio-2 éthyle ou méthylsulfinyle-2 éthyle, R'3 représente un atome d'hydrogène et R représente un atome d'hydrogène.4 - New peptides according to claim 1 for which Rj represents a 2-mercapto-ethyl or amino-1-mercapto-2-ethyl radical, Xi and Y ] each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> CO, R2 represents an isopropyl radical, X2 and Y2 each represent a hydrogen atom or form together with the carbon atom to which they are linked a group> C = O, R'2 represents an atom of hydrogen, R3 represents a 2-methylthio-ethyl or 2-methylsulfinyl-ethyl radical, R'3 represents a hydrogen atom and R represents a hydrogen atom.
5 - Composition pharmaceutique caractérisée en ce qu'elle contient une quantité suffisante d'un peptide selon l'une des revendications 1 à 4 en association avec un ou plusieurs diluants ou adjuvants pharmaceutiquement acceptables inertes ou physiologiquement actifs. 5 - Pharmaceutical composition characterized in that it contains a sufficient amount of a peptide according to one of claims 1 to 4 in combination with one or more diluents or pharmaceutically acceptable adjuvants inert or physiologically active.
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