EP0808329A1 - Inhibitoren der farnesyltransferase, ihre herstellung und sie enthaltende pharmazeutische zubereitungen - Google Patents

Inhibitoren der farnesyltransferase, ihre herstellung und sie enthaltende pharmazeutische zubereitungen

Info

Publication number
EP0808329A1
EP0808329A1 EP96903062A EP96903062A EP0808329A1 EP 0808329 A1 EP0808329 A1 EP 0808329A1 EP 96903062 A EP96903062 A EP 96903062A EP 96903062 A EP96903062 A EP 96903062A EP 0808329 A1 EP0808329 A1 EP 0808329A1
Authority
EP
European Patent Office
Prior art keywords
radical
hydrogen atom
carbon atoms
atom
alkyl
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.)
Withdrawn
Application number
EP96903062A
Other languages
English (en)
French (fr)
Inventor
François CLERC
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0808329A1 publication Critical patent/EP0808329A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new famesy] transferase inhibitors of general formula:
  • the inhibition of fainesyl transferase and, therefore, of 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 show their inhibitory activity at concentrations close to 10 "" M or 0 10-7M.
  • Rj 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 radical R4-S- in which R4 represents a radical alkyl containing 1 to 6 carbon atoms optionally substituted by a phenyl radical or a 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 4 carbon atoms, mercapto, alkylthio containing 1 to 4 carbon atoms, alkylsulfinyl containing 1 to 4 carbon atoms 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 ⁇ 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 4 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 j 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,
  • R2 represents an isopropyl, 1-methylpropyl, tert-butyl or cyclohexylmethyl radical
  • R'2 represents a hydrogen atom or a methyl radical
  • 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
  • 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,
  • Ri 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 and Yi each represent a hydrogen atom or together form with the carbon atom to which they are linked a group> CO,
  • R2 represents an isopropyl, 1-methyl propyl, tert-butyl or cyclohexyl methyl radical
  • R'2 represents a hydrogen atom
  • R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms.
  • R 1 represents a 2-mercapto-ethyl or 2-amino-2-mercapto-ethyl radical
  • Xj and Y each represent a hydrogen atom or form together with the atom of carbon to which they are linked a group> CO
  • R2 represents an isopropyl radical
  • R'2 represents a hydrogen atom
  • R3 represents a 2-methylthioethyl or 2-methylsulfinylethyl radical
  • R'3 represents a hydrogen atom
  • 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 R 3 CH (NR' 3 ) CO-OH preferably have the amino acid configuration natural.
  • 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 amide and imidazole functions by trityl groups can be carried out on a resin confined in syringes of solid phase extraction of 3 cm3 in high density polyethylene provided with teflon filters.
  • the syringes are mounted on a two-way teflon valve and closed by a disposable wing plug made 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 can be carried out on 50 ⁇ moles of resin.
  • Amino acid couplings are carried out by treating the resin for 1 hour with 250 ⁇ moles amino acid suitably protected in the presence of 250 ⁇ moles 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
  • 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.
  • Cys- (NMe) Val - [(R, S) -tetrahydro-1,2,3,4-isoquinoline-1-carbonyl] -Met can be prepared as follows: 50 ⁇ moles of Fmoc-Met resin [Wang resin;
  • 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 cm3 of a mixture of methyl-tert-butyl ether and petroleum ether (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 Cl 8,100 A column (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
  • Tetrahydro-1,2,3,4-isoquinoline-1-carboxylic acid in racemic form can be prepared by hydrogenation of isoquinoline-1-carboxylic acid under the conditions described by RT Shuman et al., J. Med . Chem., __, 314 (1993).
  • the FMOC protective group is introduced onto an amino acid by the action of the amino acid on 9-fluorenylmethyl chloroformate (FMOC-chloride) in the presence of a base.
  • the farnesyltransferase and famesylation inhibitory activity of the Ras protein can be demonstrated in the following test:
  • the farnesyltransferase activity is determined by the amount of ( ⁇ H) famesyl transferred from H) famesylpyrophosphate [H) FPP) to the p21 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, octyl- ⁇ -D-glucopyranoside 0.2%, p21 H-ras 200 picomoles, ( ⁇ H ) FPP (at 61,000 dpm / picomole) 4.5 picomoles.
  • the reaction is initiated by the addition of approximately 5 ng of human farnesyltransferase purified from cultures of THP1 cells. After incubation for 20 minutes at 37 ° C. in a microtiter 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. at 0 ° C. 0.4 cm 3 of trichloroacetic acid (TCA) 30% in methanol is then added to the mixture. The plates are left for 1 hour in ice.
  • TCA trichloroacetic acid
  • the precipitated content is then retained on a fiberglass® filtermat® membrane, 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 ⁇ -Plate® counter (LKB). Each test is repeated 3 times.
  • the activity unit is defined by 1 picomole of 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 farnesyltransferase 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 one or more diluents or pharmaceutically acceptable adjuvants whether inert or physiologically active.
  • compositions can be administered orally, parenterally or rectally.
  • 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.
  • compositions for oral administration can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil.
  • 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.
  • the 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.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP96903062A 1995-02-09 1996-02-07 Inhibitoren der farnesyltransferase, ihre herstellung und sie enthaltende pharmazeutische zubereitungen Withdrawn EP0808329A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9501490 1995-02-09
FR9501490A FR2730492B1 (fr) 1995-02-09 1995-02-09 Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
PCT/FR1996/000199 WO1996024612A1 (fr) 1995-02-09 1996-02-07 Inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent

Publications (1)

Publication Number Publication Date
EP0808329A1 true EP0808329A1 (de) 1997-11-26

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EP96903062A Withdrawn EP0808329A1 (de) 1995-02-09 1996-02-07 Inhibitoren der farnesyltransferase, ihre herstellung und sie enthaltende pharmazeutische zubereitungen

Country Status (16)

Country Link
EP (1) EP0808329A1 (de)
JP (1) JPH10513468A (de)
KR (1) KR19980702049A (de)
CN (1) CN1173873A (de)
AU (1) AU4722896A (de)
BR (1) BR9607318A (de)
CA (1) CA2210953A1 (de)
CZ (1) CZ249997A3 (de)
FI (1) FI973279A0 (de)
FR (1) FR2730492B1 (de)
NO (1) NO973607D0 (de)
PL (1) PL321710A1 (de)
SK (1) SK108897A3 (de)
TR (1) TR199700726T1 (de)
WO (1) WO1996024612A1 (de)
ZA (1) ZA961073B (de)

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ZA961073B (en) 1996-08-20
FI973279A7 (fi) 1997-08-08
CZ249997A3 (en) 1997-11-12
JPH10513468A (ja) 1998-12-22
CN1173873A (zh) 1998-02-18
WO1996024612A1 (fr) 1996-08-15
AU4722896A (en) 1996-08-27
NO973607L (no) 1997-08-05
BR9607318A (pt) 1997-12-30
FI973279A0 (fi) 1997-08-08
TR199700726T1 (xx) 1998-01-21
MX9705969A (es) 1997-11-29
FR2730492A1 (fr) 1996-08-14
PL321710A1 (en) 1997-12-22
SK108897A3 (en) 1997-12-10
KR19980702049A (ko) 1998-07-15
NO973607D0 (no) 1997-08-05
FR2730492B1 (fr) 1997-03-14
CA2210953A1 (fr) 1996-08-15

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