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WO1997005270A1 - Inhibiteurs de farnesyl proteine-transferase - Google Patents

Inhibiteurs de farnesyl proteine-transferase Download PDF

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Publication number
WO1997005270A1
WO1997005270A1 PCT/US1996/012114 US9612114W WO9705270A1 WO 1997005270 A1 WO1997005270 A1 WO 1997005270A1 US 9612114 W US9612114 W US 9612114W WO 9705270 A1 WO9705270 A1 WO 9705270A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
preparation
recited
pharmaceutically acceptable
Prior art date
Application number
PCT/US1996/012114
Other languages
English (en)
Inventor
Carmen Cascales
Russell B. Lingham
Fernando Pelaez
Jon D. Polishook
Keith C. Silverman
Sheo B. Singh
Deborah L. Zink
Original Assignee
Merck & Co., Inc.
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
Priority claimed from GBGB9606502.4A external-priority patent/GB9606502D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU65940/96A priority Critical patent/AU706341B2/en
Priority to EP96925425A priority patent/EP0842291A4/fr
Priority to CA002227369A priority patent/CA2227369A1/fr
Priority to JP9507688A priority patent/JPH11510388A/ja
Publication of WO1997005270A1 publication Critical patent/WO1997005270A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin

Definitions

  • Ras gene is found activated in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein, since Ras must be localized in the plasma membrane and must bind with GTP in order to transform cells (Gibbs, J. et al., Microbiol. Rev. 53: 171 -286 ( 1989)). Forms of Ras in cancer cells have mutations that distinguish the protein from Ras in normal cells.
  • Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 370:583-586 (1984)).
  • Other proteins having this motif include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin.
  • Ha-Ras and N-Ras are palmitoylated via formation of a thioester on a Cys residue near a C-terminal Cys farnesyl acceptor (Gutierrez et al., EMBO J. 5:1093- 1098 ( 1989); Hancock et al., Cell 57:1 167-1171 (1989)). Ki-Ras lacks the palmitate acceptor Cys. The last 3 amino acids at the Ras C-terminal end are removed proteolytically, and methyl esterification occurs at the new C-terminus (Hancock et al., ibid). Fungal mating factor and mammalian nuclear lamins undergo identical modification steps (Anderegg et al., J. Biol. Chem.
  • Inhibition of farnesyl-protein transferase and, thereby, of famesylation of the Ras protein blocks the ability of Ras to transform normal cells to cancer cells.
  • the compounds of the invention inhibit Ras famesylation and, thereby, generate soluble Ras which, as indicated infra, can act as a dominant negative inhibitor of Ras function. While soluble Ras in cancer cells can become a dominant negative inhibitor, soluble Ras in normal cells would not be an inhibitor.
  • a cytosol-localized (no Cys-Aaa 1 -Aaa 2 -Xaa box membrane domain present) and activated (impaired GTPase activity, staying bound to GTP) form of Ras acts as a dominant negative Ras inhibitor of membrane-bound Ras function (Gibbs et al., Proc. Natl. Acad. Sci. USA 56:6630-6634(1989)). Cytosollocalized forms of Ras with normal GTPase activity do not act as inhibitors. Gibbs et al., ibid, showed this effect in Xenopus oocytes and in mammalian cells.
  • cytosolic pool of Ras In tumor cells having activated Ras, the cytosolic pool acts as another antagonist of membrane-bound Ras function. In normal cells having normal Ras, the cytosolic pool of Ras does not act as an antagonist. In the absence of complete inhibition of famesylation, other farnesylated proteins are able to continue with their functions.
  • Farnesyl-protein transferase activity may be reduced or completely inhibited by adjusting the compounds dose. Reduction of farnesyl-protein transferase enzyme activity by adjusting the compounds dose.
  • Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group.
  • Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in vivo and inhibits Ras function.
  • CA 1 A 2 X-type FPTase inhibitors contain acyclic amino acids in the second position. Incorporation of proline in the Al position in such inhibitors has been shown to be the least well tolerated amino acid substitution in that position (Reiss et al., PNAS (1991)).
  • Such inhibitors may inhibit while serving as alternate substrates for the Ras farnesyl-transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas).
  • Inhibitors of farnesyl protein transferase which are citraconic acid derivatives have been isolated as fermentation products from a strain of Chaetomella acutiseta (U.S. Pat. No. 5,260,479 and EP-547671 -A). Synthetic analogs of those compounds have also been described (U.S. Pat. Nos. 5,245,061 and 5,260,479).
  • Non-peptide compounds that are inhibitors of Ras farnesyl-protein transferase have been isolated from a strain of Cylindocarpon lucidum (U.S. Pat. No. 5,420,334).
  • the present invention relates to compounds which inhibit farnesyl-protein transferase and the famesylation of the oncogene protein Ras, chemotherapeutic compositions containing the compounds of this invention, and methods for producing the compounds of this invention.
  • R 1 is H, or C 1 -C 4 alkyl
  • R 3 is C 1 -C 4 alkyl ; or the pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • R 1 is H, or C 1 -C 4 alkyl; or the pharmaceutically acceptable salt, hydrate or prodrug.
  • R 3 is C 1 -C 4 alkyl ; or the pharmaceutically acceptable salt, hydrate or prodrug thereof.
  • Compound A has the formula:
  • Compound B has the formula:
  • Compound H has the formula:
  • Compound I has the formula:
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • alkyl includes methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl and the like.
  • mutants of the above described organism may also be capable of producing the compounds of this invention.
  • the culture MF 61 18 is that of a fungus, Phoma sp., isolated from leaf litter of the desert shrub, Zygophyllum staffii, collected in Omdel, Thailand. This culture has been deposited with the American Type Culture Collection at 12301 Parklawn Drive, Rockville, MD 20852 as ATCC 74347.
  • Conidiogenous cells ampulliform, phialidic.
  • Conidia predominately elliptical, sometimes obovate, dumbbell shaped or cylindrical, hyaline, guttules at each end, 4 - 5 ⁇ 1 - 2 ⁇ m.
  • Phoma Coelomycetes, Deuteromycotina
  • MF 6118 exhibits all of the aforementioned generic characteristics but, in culture, does not exhibit any distinguishing characteristics to confidently place this fungus in a particular species. Therefore, it is designated as Phoma sp.
  • Nutrient media may also contain
  • the preferred sources of carbon in the nutrient medium are sucrose or fructose.
  • the preferred sources of carbon in the nutrient medium are sucrose or fructose.
  • trace metals such as manganese, iron,
  • the fermentation production medium is incubated for about 3 to 30 days, preferably about 12 to 21 days.
  • the fermentation is conducted aerobically at temperatures ranging from about 20 to 30°C. To obtain optimum results, the temperatures are in the range of about 22 to 28°C, most preferably about 22 to 25°C.
  • fermentation flasks are harvested and the active compound isolated.
  • the compounds is useful as a pharmaceutical agent for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this
  • Step C Isolation and Purification of 7-hydroxy-9-methyl-6-oxo6H-oxepino[2,3-b][1]benzopyran-5-carboxylic acid methyl ester

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des composés non peptidiques qui inhibent la farnésyl protéine-transférase (FPTase) et la farnésylation de la protéine oncogène ras. Elle porte aussi sur le procédé de préparation d'un composé selon l'invention par mise en culture de Phoma sp, ainsi que sur des compositions chimiothérapeutiques contenant lesdits composés et des procédés pour inhiber la farnésyl protéine-transférase et la farnésylation de la protéine oncogène Ras.
PCT/US1996/012114 1995-07-25 1996-07-22 Inhibiteurs de farnesyl proteine-transferase WO1997005270A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU65940/96A AU706341B2 (en) 1995-07-25 1996-07-22 Inhibitors of farnesyl-protein transferase
EP96925425A EP0842291A4 (fr) 1995-07-25 1996-07-22 Inhibiteurs de farnesyl proteine-transferase
CA002227369A CA2227369A1 (fr) 1995-07-25 1996-07-22 Inhibiteurs de farnesyl proteine-transferase
JP9507688A JPH11510388A (ja) 1995-07-25 1996-07-22 ファルネシル−タンパク質転移酵素の阻害剤

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US141495P 1995-07-25 1995-07-25
US60/001,414 1995-07-25
GB9606502.4 1996-03-28
GBGB9606502.4A GB9606502D0 (en) 1996-03-28 1996-03-28 Inhibitors of farnesyl-protein transferase

Publications (1)

Publication Number Publication Date
WO1997005270A1 true WO1997005270A1 (fr) 1997-02-13

Family

ID=26309006

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/012114 WO1997005270A1 (fr) 1995-07-25 1996-07-22 Inhibiteurs de farnesyl proteine-transferase

Country Status (5)

Country Link
EP (1) EP0842291A4 (fr)
JP (1) JPH11510388A (fr)
AU (1) AU706341B2 (fr)
CA (1) CA2227369A1 (fr)
WO (1) WO1997005270A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5082489A (en) * 1990-02-06 1992-01-21 The Royal Institution For The Advancement Of Learning (Mcgill University) Composition for biocontrol of wild buckwheat
US5151529A (en) * 1988-11-28 1992-09-29 Sankyo Company, Limited Platelet activating factor antagonists, named "the phomactins" their preparation and use
US5254727A (en) * 1992-10-19 1993-10-19 Merck & Co., Inc. Acyclic tricarboxylic acid compounds
US5310949A (en) * 1992-09-02 1994-05-10 Merck & Co., Inc. Cholesterol lowering compounds
US5364948A (en) * 1991-08-02 1994-11-15 Merck & Co., Inc. Biologically active compounds isolated from aerobic fermentation of Trichoderma viride
US5498627A (en) * 1994-04-15 1996-03-12 Takeda Chemical Industries, Ltd. Octahydro-2-naphthalenecarboxylic acid derivative, its production and use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5151529A (en) * 1988-11-28 1992-09-29 Sankyo Company, Limited Platelet activating factor antagonists, named "the phomactins" their preparation and use
US5082489A (en) * 1990-02-06 1992-01-21 The Royal Institution For The Advancement Of Learning (Mcgill University) Composition for biocontrol of wild buckwheat
US5364948A (en) * 1991-08-02 1994-11-15 Merck & Co., Inc. Biologically active compounds isolated from aerobic fermentation of Trichoderma viride
US5310949A (en) * 1992-09-02 1994-05-10 Merck & Co., Inc. Cholesterol lowering compounds
US5254727A (en) * 1992-10-19 1993-10-19 Merck & Co., Inc. Acyclic tricarboxylic acid compounds
US5498627A (en) * 1994-04-15 1996-03-12 Takeda Chemical Industries, Ltd. Octahydro-2-naphthalenecarboxylic acid derivative, its production and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0842291A4 *

Also Published As

Publication number Publication date
EP0842291A4 (fr) 1998-11-11
AU6594096A (en) 1997-02-26
CA2227369A1 (fr) 1997-02-13
AU706341B2 (en) 1999-06-17
EP0842291A1 (fr) 1998-05-20
JPH11510388A (ja) 1999-09-14

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