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WO1997036879A1 - Inhibiteurs de transferase de farnesyl-proteine - Google Patents

Inhibiteurs de transferase de farnesyl-proteine Download PDF

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Publication number
WO1997036879A1
WO1997036879A1 PCT/US1997/005240 US9705240W WO9736879A1 WO 1997036879 A1 WO1997036879 A1 WO 1997036879A1 US 9705240 W US9705240 W US 9705240W WO 9736879 A1 WO9736879 A1 WO 9736879A1
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Prior art keywords
substituted
unsubstituted
alkyl
hydrogen
cycloalkyl
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PCT/US1997/005240
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English (en)
Inventor
Samuel L. Graham
Neville J. Anthony
John S. Wai
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Merck & Co., Inc.
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Priority claimed from GBGB9614316.9A external-priority patent/GB9614316D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU25559/97A priority Critical patent/AU2555997A/en
Priority to JP9535513A priority patent/JP2000507587A/ja
Priority to EP97917131A priority patent/EP0891337A1/fr
Publication of WO1997036879A1 publication Critical patent/WO1997036879A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

Definitions

  • Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is
  • Mutated ras genes (Ha-ras, Ki4a-r ⁇ s, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
  • Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 570:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C 20 isoprenoid, respectively.
  • farnesyl-protein transferase or geranylgeranyl-protein transferase which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C 20 isoprenoid, respectively.
  • farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are
  • Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al, Cell, 62:81 -88 ( 1990); Schaber et al, J. Biol Chem., 265:14701-14704 (1990); Schafer et al, Science, 249: 1133-1 139 (1990); Marine et al, Proc. Natl Acad. Sci USA, 87:7541-7545 (1990)).
  • Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of farnesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, 88:732-736 (1991)).
  • Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.
  • FPTase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-1 12930).
  • the present invention comprises peptidomimetic benzodiazepine-containing compounds which inhibit the famesyl-protein transferase.
  • the instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity.
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras.
  • the inhibitors of famesyl-protein transferase are illustrated by the formula: wherein:
  • R b is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 1 a and R 1 b are independently selected from:
  • R 2 is selected from
  • substitutent on the substituted C 1 -C 6 alkyl is selected from halogen, unsubstituted or substituted aryl, heterocyclic, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 3 is selected from a sidechain of a natural amino acid
  • R 4 and R 4a are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from halogen, unsubstituted or substituted aryl, heterocyclic, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 5 is selected from :
  • substitutent on the substituted C 1 -C 6 alkyl is selected from halogen, unsubstituted or substituted aryl, heterocyclic, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 8 is selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, CN, H 2 N- C(NH)-, R 10 C(O)-, R 1 0 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 9 is selected from:
  • R 10 is selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 1 1 is selected from C 1 -C 6 alkyl and aryl;
  • Q is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, halogen C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O)m-, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN,
  • V is selected from:
  • V is not hydrogen if A l is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is selected from: a) hydrogen,
  • substitutent on the substituted C 1 -C 8 alkyl is selected from halogen, unsubstituted or substituted aryl, heterocyclic, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O)m-, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN,
  • R 4 , R 4a and W taken together are hydrogen;
  • Z is a heterocycle; m is 0, 1 or 2;
  • n 0, 1 , 2, 3 or 4;
  • p 0, 1 , 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; and u is 0 or 1;
  • Ras farnesyl transferase inhibitors of formula I contain the following substituents:
  • R b is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 3 is selected from the side chain of methionine, serine, glutamine, leucine and phenylalanine;
  • R 4 and R4a are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 5 is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, halogen, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN,
  • X is -CH 2 - ; or the pharmaceutically acceptable salts thereof.
  • R b is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 1 1 S(O) m -, R 10 C(O)N R 10 -, (R 10 ) 2 N-C(O)-, CN,
  • R 3 is selected from the side chain of methionine, serine, glutamine, leucine and phenylalanine;
  • R 4 and R4a are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 5 is selected from:
  • R 9a is hydrogen or methyl
  • Q is selected from:
  • R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 1 0 OC(O)-,
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, halogen, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O)m-, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 ,
  • X is -CH 2 - ; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of famesyl-protein transferase are illustrated by the formula B:
  • R b is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 ,
  • R 3 is selected from methionine,serine, glutamine, leucine and
  • R 4 and R4a are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 5 is selected from:
  • R 8 is selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and
  • Q is selected from:
  • R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-.
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, halogen, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 1 0 OC(O)-, N 3 ,
  • X is -CH 2 - ; or the pharmaceutically acceptable salts thereof.
  • R b is selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C6 alkynyl, R 10 O-,
  • R 3 is selected from the side chain of methionine, serine, glutamine, leucine and phenylalanine;
  • R 4 and R4a are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 5 is selected from:
  • Q is selected from:
  • R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-,
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, halogen, C 3 - C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(O)-, CN,
  • X is -CH 2 - ; or the pharmaceutically acceptable salts thereof.
  • the preferred compounds of this invention include
  • amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds.
  • alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl groups include phenyl, naphthyl, anthracenyl, biphenyl,
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 1 1 - membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,
  • substituted aryl substituted heterocycle
  • substituted cycloalkyl are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF 3 , NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • -N(R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
  • the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol.
  • Such benzodiazepine analogs may be synthesized by techniques well known in the art. General methods of synthesis of the benzediazapine analogs of this invention are shown in Schemes 1 , 2 and 3. Typically a convergent route is employed, which joins the key intermediate 6 (Scheme 2) and R a and R b components (Schemes 2 and 3) using standard bond-forming procedures.
  • the amine 6 may be prepared from a suitably substituted 2-aminobenzoketone (2).
  • Many 2- aminobenzoketones are known in the art or are available form
  • the amide 3 may be alkylated at N-1 with an appropriate alkyl halide in the presense of a base such as cesium carbonate to afford the amide 4.
  • the amide 4 can be converted to the amine 6 via a two step protocol. Electrophillic azidination of the enolate anion generated by treatment of 4 with strong base such as sodium hexamethyl disilazide. with triisopropylbenzenesulfonylazide . Reduction of the azide by treatment of 5 with triphenylphosphine in aqueous THF affords the amine 6.
  • the amine 6 may be derivatized by acylation, reductive amination or alkylation to afford compounds of this invention (scheme 2). The syntheses of the required acylating, and alkylating reagents are shown in schemes 4, 5 and 6.
  • the instant compounds are useful as pharmaceutical agents 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 invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
  • Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e.,
  • NF-1 neurofibromin
  • neu neu
  • ser ser
  • abl abl
  • lck lck
  • fyn fyn
  • the compounds of the instant invention inhibit famesyl- protein transferase and the famesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
  • Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF-1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffher et al.
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the compounds of the instant invention may also be co- administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
  • Such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the
  • compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
  • pharmacologically acceptable carriers e.g., saline
  • the solutions may be introduced into a patient's blood-stream by local bolus injection.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.
  • FPTase famesyl-protein transferase
  • composition to be tested may be divided and the two
  • mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • the chemical content of the assay mixtures may be determined by well known
  • inhibitors of FPTase absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine whether the enzyme has been modified or modified by the enzyme's activity.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the
  • concentration of enzyme in the assay vessel required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
  • Step A 1 -Triphenylmethyl-4-(hydroxymethyl)-imidazole
  • Step B 1-Triphenylmethyl-4-(acetoxymethyl)-imidazole
  • the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 °C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 °C. After two hours, the solution was reconcentrated in vacuo to provide a solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a solid which was used in the next step without further purification.
  • Step E 1 -(4-Cyanobenzyl)-5-imidazolecarboxaldehyde
  • Step F 2.3-Dihydro-2-oxo-5-phenyl-1H-1 ,4-benzo-diazepine 1
  • Step G 2,3-Dihydro- 1 -(2,2,2-trifluoroethyl)-2-oxo-5-phenyl-1H-
  • Step H 3-Azido-5-phenyl-1-(2,2,2-trifluoroethyl)-1H- benzo[e] [1 ,4] diazepine
  • Step J 2-(R)-2-amino-N-[3R-2-oxo-5-phenyl-1- (2,2,2- trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3- yl]-3-phenyl-propionamide and 2-(R)-2-amino-N-[3(S)-2- oxo-5-phenyl-1 - (2,2,2-trifluoroethyl)-2,3-dihydro-1H- benzo[e][ 1,41diazepin-3-yl]-3-phenyl-propionamide
  • Step K 3-(R)-(+)-3-amino-5-phenyl-1 -(2,2,2-trifluoro- ethyl)-H- benzo[ e][1,4] diazepine
  • Step L 3S-(+)-3-Amino-5-phenyl-1-(2,2,2-trifluoro-ethyl)-H- benzo[e][1,4] diazepine
  • Step M 3(R)-3- ⁇ 1-(4-Cyanobenzyl)imidazol-5-yl-methylamino ⁇ - 5-phenyl-1-(2,2,2-trifluoroethyl)-H-benzo[e][1,4] diazepine
  • stepK 3(R)-3- ⁇ 1-(4-Cyanobenzyl)imidazol-5-yl-methylamino ⁇ - 5-phenyl-1-(2,2,2-trifluoroethyl)-H-benzo[e][1,4] diazepine
  • Step B 1-(Triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester
  • Step D [1 -(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid
  • Step E 3(R)-3- ⁇ 1-(4-Cyanobenzyl) imidazol-5-yl-acety]amino ⁇ -5- phenyl-1 -(2,2,2-trifluoroethyl)-H-benzo[e][1 ,4] diazepine
  • 3(R)-(+)-3-amino-5-phenyl- 1 -(2,2,2- trifluoroethyl)-H-benzo[e][1 ,4] diazepine from example 1 , step K) (100.5mg, 0.302mmol), [ 1 -(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid (from step D) (85.9mg, 0.303mmol), HOOBT (60.4mg, 0.37mmol) and triethylamine (0.10ml, 0.717mmol) in DMF (3ml) was added EDC (71mg, 0.37
  • a solution of 3-amino-2,3-dihydro-2-oxo-5-phenyl-1H -1 ,4 -benzodiazepine hydrogen bromide (142 mg, 0.426 mmol), prepared by sequential treatment of an aqueous acetonitrile solution of the 4-methoxybenzyl derivative from example 5 with ammonium cerium IV nitrate, potassium tartrate solution and HBr/acetic acid - (L)- pyroglutamic acid (60.2 mg, 0.466 mmol), EDC (91 mg, 0.473 mmol), HOBT (63.5 mg, 0.473 mmol), and diisopropylethylamine (0.082ml, 0.473 mmol) in DMF (5 ml) was stirred at room temperature for 18 hours.
  • Lyophilization provided the titled compound as a 1 : 1 mixture of diastereomers.
  • step C To a stirred solution of the ester from example 3, step C, (1.50g, 5.88mmol), in methanol (20ml) at 0°C, was added sodium borohydride (1.0g, 26.3mmol) portionwise over 5 minutes. The reaction was stirred at 0°C for 1 hr and then at room temperature for an additional 1 hr. The reaction was quenched by the addition of sat.NH4Cl solution and the methanol evaporated in vacuo. The residue wsas partitioned between EtOAc and sat NaHC ⁇ 3 solution and the organic extracts dried (MgSO 4 ) and evaporated in vacuo.
  • Step B 5-(-1 -(4-Cyanobenzyl)-imidazolyl)ethyl methanesulfonate
  • Step C 3(R)-3-[ 1-(4-Cyanobenzyl) imidazol-5-yl-ethylamino-]-5- phenyl-1 -(2,2,2-trifluoroethyl)-H-benzo[e][ 1 ,4] diazepine
  • a mixture of 3R-(+)-3-amino-5-phenyl-1 -(2,2,2- trifluoroethyl)-H-benzo[el[1 ,4] diazepine from example 1 , step K) (99.5mg, 0.299mmol), 5-(-1 -(4-Cyanobenzyl)-imidazolyl)ethyl methanesulfonate (from step B) (94.5mg, 0.309mmol), K 2 CO 3 (108mg,
  • Partially purified bovine FPTase and Ras peptides were prepared as described by Schaber et al, J. Biol Chem. 265.14701-14704 (1990), Pompliano, et al, Biochemistry 31 :3800 (1992) and Gibbs et al, PNAS U.S.A.
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl 2 , 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-famesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min.
  • HEPES N-(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid)
  • DTT dithiothreitol
  • [ 3 H]-famesyl diphosphate [ 3 H]-FPP; 740 CBq/mmol, New England Nuclear
  • Ras-CVLS 10 ⁇ g
  • Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ -plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [ 3 H]-FPP was utilized during the reaction period.
  • DMSO dimethyl methyl sulfoxide
  • Human FPTase was prepared as described by Omer et al, Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • Examples 1 -10 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC 50 of ⁇ 100 ⁇ M.
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al, Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
  • the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35s]methionine (1000 Ci/mmol).
  • the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM DTT/10 mg/ml aprotinen/2 mg/ml leupe ⁇ tin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y 13-259 (Furth, M.E. et al, J. Virol.
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
  • the cells are fed twice weekly with 0.5 ml of medium A containing 0.1 % memanol or the concentration of the instant compound.
  • Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

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Abstract

Cette invention concerne des composés substitués de benzodiazépine permettant d'inhiber la transférase de farnésyl-protéine (FTase), ainsi que la farnésylation de la protéine oncogène Ras. Cette invention concerne également des compositions chimiothérapeutiques contenant les composés susmentionnés, ainsi que des procédés permettant d'inhiber la transférase de farnésyl-protéine et la farnésylation de la protéine oncogène Ras.
PCT/US1997/005240 1996-04-03 1997-03-31 Inhibiteurs de transferase de farnesyl-proteine WO1997036879A1 (fr)

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AU25559/97A AU2555997A (en) 1996-04-03 1997-03-31 Inhibitors of farnesyl-protein transferase
JP9535513A JP2000507587A (ja) 1996-04-03 1997-03-31 ファルネシルタンパク質トランスフェラーゼ阻害剤
EP97917131A EP0891337A1 (fr) 1996-04-03 1997-03-31 Inhibiteurs de transferase de farnesyl-proteine

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US1459496P 1996-04-03 1996-04-03
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GBGB9614316.9A GB9614316D0 (en) 1996-07-08 1996-07-08 Inhibitors of farnesyl-protein transferase
GB9614316.9 1996-07-08

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US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
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US5532359A (en) * 1993-05-14 1996-07-02 Genentech, Inc. Ras farnesyl transferase inhibitors

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