WO1997038664A2 - Methode de traitement de cancer - Google Patents

Methode de traitement de cancer Download PDF

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Publication number
WO1997038664A2
WO1997038664A2 PCT/US1997/006248 US9706248W WO9738664A2 WO 1997038664 A2 WO1997038664 A2 WO 1997038664A2 US 9706248 W US9706248 W US 9706248W WO 9738664 A2 WO9738664 A2 WO 9738664A2
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Prior art keywords
methionine
glycyl
pyrrolidin
substituted
ylmethyl
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PCT/US1997/006248
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English (en)
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WO1997038664A3 (fr
Inventor
Jackson B. Gibbs
Nancy E. Kohl
Allen I. Oliff
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Merck & Co., Inc.
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Priority claimed from GBGB9611982.1A external-priority patent/GB9611982D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97922313A priority Critical patent/EP0952842A2/fr
Priority to AU28022/97A priority patent/AU2802297A/en
Priority to JP09537313A priority patent/JP2000513711A/ja
Publication of WO1997038664A2 publication Critical patent/WO1997038664A2/fr
Publication of WO1997038664A3 publication Critical patent/WO1997038664A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • 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
    • A61K38/05—Dipeptides
    • 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
    • A61K38/06—Tripeptides
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a method of treating cancer using a combination of a compound which is a inhibitor of geranylgeranyl-protein transferase-type I and a compound which is a inhibitor of farnesyl-protein transferase.
  • the invention further relates to a method of treating cancer using a combination of a compound which is a selective inhibitor of geranylgeranyl-protein transferase-type I and a compound which is a selective inhibitor of farnesyl-protein transferase.
  • Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a new class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C.
  • Prenylated proteins share characteristic C-terminal sequences including CaaX (C, Cys; a, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC.
  • Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-terminal to the farnesylated Cys. Proteins terminating with a XXCC or XCXC motif are modified by geranylgeranylation on the Cys residues and do not require an endoproteolytic processing step. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxymethylation follows prenylation of proteins terminating with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61 , 355-386).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl- protein transferase type I
  • Rab GGPTase geranylgeranyl-protein transferase type-II
  • FPTase and GGPTase-I are ⁇ / ⁇ heterodimeric enzymes that share a common ⁇ subunit; the ⁇ subunits are distinct but share approximately 30% amino acid similarity (Brown, M. S. and Goldstein, J. L. (1993). Nature 366, 14-15; Zhang, F. L., Diehl, R. E., Kohl, N. E., Gibbs, J. B., Giros, B., Casey, P. J., and Omer, C. A. (1994). J. Biol. Chem. 269, 3175-3180).
  • GGPTase-II has different ⁇ and ⁇ subunits and complexes with a third component (REP, Rab Escort Protein) that presents the protein substrate to the ⁇ / ⁇ catalytic subunits.
  • REP Rab Escort Protein
  • Each of these enzymes selectively uses farnesyl diphosphate or geranylgeranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate.
  • FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gin or Ala.
  • CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme.
  • GGPTase-II modifies XXCC and XCXC proteins; the interaction between GGPTase-II and its protein substrates is more complex, requiring protein sequences in addition to the C-terminal amino acids for recognition.
  • the enzymological characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E.,
  • the Ras protein is 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 terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851 -891 (1993)).
  • Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 277 :810-812).
  • Mutated ras genes 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.
  • the Ras protein is one of several proteins that are known to undergo post-translational modification.
  • 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, 249:1 133-1 139 (1990); Marine et al., Proc. Natl. Acad. Sci USA, 87:7541 -7545 (1990)).
  • Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
  • the 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 310 :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.
  • N- Ras and K-Ras proteins' sequences do not exhibit the absolute substrate specificity for farnesyl-protein transferase that is found for the H-Ras C-terminus sequence, which allows N-Ras and K-Ras proteins to be processed bygeranylgeranyl-protein transferase as well (Moores, S. L. et al., J. Biol. Chem., 266:17438 ( 1991 ) and James, G. et al., J. Biol. Chem., 270:6221 -6226 (1995)).
  • 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.
  • GTP-binding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol.
  • GGTase-I Protein geranylgeranyltransferase type-I transfers a geranylgeranyl group from the prenyl donor geranylgeranyl diphosphate to the cysteine residue of substrate proteins containing a C-terminal CAAX -motif in which the "X" residue is leucine or phenyl- alanine (Clark, 1992; Newman and Magee, 1993).
  • Known targets of GGTase-I include the gamma subunits of brain heterotrimeric
  • RhoA, RhoB, RhoC, CDC42Hs Ras-related small GTP-binding proteins
  • RhoA, RhoB, RhoC, CDC42Hs Ras-related small GTP-binding proteins
  • RhoA, RhoB, RhoC, CDC42Hs Ras-related small GTP-binding proteins
  • RhoA, RhoB, RhoC, CDC42Hs have roles in the regulation of cell shape (Ridley, A. J. and Hall, A. (1992). Cell 70:389-399; Ridley, A. J., Paterson, H. F., Johnston, C. L., Keikmann, D., and Hall, A.
  • Rho and Rac proteins transmit intracellular signals initiated by growth factors and by Ras protein (Prendergast, G. C. and Gibbs, J. B. (1993). Adv. Cancer Res. 62, 19-64; Ridley and Hall, 1992; Ridley et al., 1992).
  • Rho and Rac proteins were required by Ras and growth factors to change cell shape, a biological parameter indicative of cellular transformation and cancer.
  • Activated forms of Rho and Rac proteins have also been shown to cause cellular transformation in cell culture (Symons, M., Current Opinion Biotechnology, 6:668-674 (1995)). Since Rho and Rac proteins require geranylgeranylation for function, an inhibitor of GGPTase-I would block the functions of these proteins and be useful as an anticancer agent.
  • FPTase farnesyl-protein transferase
  • the first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme.
  • FPP farnesyl diphosphate
  • 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 alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas; N.E. Kohl et al. , Science, 260 : 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • Mammalian cells express four types of Ras proteins (H-, N, K4A-, and K4B-Ras) among which K-Ras4B is the most frequently mutated form of Ras in human cancers.
  • Inhibition of farnesyl-protein transferase has been shown to block the growth of H-ras -transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the H-Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260: 1934- 1937 (1993) and G.L. James et al., Science, 260: 1937-1942 ( 1993).
  • geranylgeranyl-protein transferase-type I inhibitor and a farnesyl- protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells that are less susceptable to treatment by one of the selective inhibitors whin administered alone.
  • a method of treating cancer is disclosed which is a
  • a mammalian patient in need of such treatment an effective amount of a combination of a geranylgeranyl- protien transferase-type I inhibitor and a farnesyl protein transferase inhibitor.
  • a selective geranylgeranyl-protein transferase- type I inhibitor and a selective farnesyl protein transferase inhibitor are used in such a combination.
  • Assays that are illustrated include in vivo prenylation inhibition by a selective FPTase inhibitor (Compound 5), a selective geranylgeranyl- protein transferase-type I inhibitor (Compound 1 ) and a non-selective inhibitor (Compound 7).
  • the intensities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein.
  • Figure 2. Autoradiograph of the 13% acrylamide gel chromatography of the immunoprecipitates from Assay Set No. 2, which includes in vivo prenylation inhibition by a combination of a selective FPTase inhibitor (Compound 5) and a selective
  • prenylated and nonprenylated Ras proteins are compared to
  • the present invention relates to a method of treating cancer which is comprised of admininstering to a mammalian patient in need of such treatment an effective amount of a combination of a geranylgeranyl-protein transferase-type I inhibitor and a farnesyl- protein transferase inhibitor.
  • the present method of treating cancer by simultaneously inhibiting farnesyl-protein transferase and
  • geranylgeranyl-protein transferase-type I offers advantages over previously disclosed methods utilizing prenyl-protein transferase inhibitors, in that the inhibitory activity of the instant combination of inhibitors against FPTase and/or GGTase can be varied by formulation depending on the nature of the cancer cells to be treated.
  • variable inhibitory potency combinations are useful in treatment of human cancers associated with the K-Ras4B and N-Ras mutated forms of Ras whose processing are not blocked by a potent selective FPTase inhibitor alone.
  • Any compound which inhibits geranylgeranyl-protein transferase-type I and any compound which inhibits farnesyl protein transferase can be used in the instant method.
  • the instant method Preferably the
  • geranylgeranyl-protein transferase- type I inhibiting compound refers to compounds which antagonize, inhibit or counteract the activity of the gene coding geranylgeranyl- protein transferase-type I or the protein produced in response thereto.
  • farnesyl protein transferase inhibiting compound likewise refers to compounds which antagonize, inhibit or counteract the activity of the gene coding farnesyl-protein transferase or the protein produced in response thereto.
  • a geranylgeranyl-protein transferase-type I inhibitor may be distinquished from a farnesyl-protein transferase inhibitor by having greater inhibitory activity against geranylgeranyl- protein transferase-type I than against farnesyl-protein transferase.
  • a farnesyl-protein transferase inhibitor may be distinquished from a geranylgeranyl-protein transferase-type I inhibitor by having greater inhibitory activity against farnesyl-protein transferase than against geranylgeranyl-protein transferase-type I.
  • selective as used herein refers to the inhibitory activity of the particular compound against geranylgeranyl-protein transferase-type I activity when compared to the inhibitory activity of the compound against farnesyl-protein transferase activity.
  • a compound is considered a selective inhibitor of geranylgeranyl-protein transferase-type I, for example, when its in vitro activity, as assessed by the assay described in Example 16, is at least 10 times greater that the in vitro acitivity of the same compound against farnesyl-protein transferase in that assay.
  • a compound is considered a selective inhibitor of farnesyl-protein transferase, for example, when its in vitro farnesyl- protein transferase inhibitory activity, as assessed by the assay described in Example 16, is at least 10 times greater that the in vitro acitivity of the same compound against geranylgeranyl-protein transferase-type I in that assay.
  • a selective compound exhibits at least 20 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition. More preferably the selectivity is at least 100 times or more.
  • the extent of selectivity of the two inhibitors that comprise the method of the instant invention effects the advantages that the method of treatment claimed herein offers over previously disclosed non-selective inhibitors of prenyl -transferase enzymes.
  • use of two independent inhibitor components that have complementary, essentially non-overlapping inhibitory activities allows the person utilizing the instant method of treatment to independently and accurately vary the inhibitory activity of the combination without having to synthesize a single drug having a particular GGTase-type I/FPTase inhibitory profile.
  • Cancers which are treatable in accordance with the invention described herein include cancers of the brain, breast, colon, genitourinary tract, lymphatic system,pancreas, rectum, stomach, larynx, liver and lung, and chronic myelogenous leukemia. More particularly, such cancers include histiocytic lymphoma, lung
  • adenocarcinoma adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma
  • the pharmaceutical composition of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected combination or compounds 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 corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com starch.
  • aqueous suspensions are required for oral use, the active ingredients are 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 combinations 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 combinations may be useful in combination with other known anti-cancer and cytotoxic agents.
  • combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple 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 pharmacolo- gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
  • pharmacolo- gically 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 a geranylgeranyl-protein transferase-type I inhibitor and a farnesyl- protein transferase inhibitor are administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount of each type of inhibitor of 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.
  • R 1 and R 2 are independently selected from:
  • R 3 is selected from alkyl, alkenyl and alkynyl of 1 to 6 carbon atoms, either branched or straight chain, which is unsubstituted or substituted with a phenyl group; and Z is H 2 or O;
  • Examples of farnesyl protein transferase inhibiting compounds and in particular selective farnesyl protein transferase inhibiting compounds include the following:
  • R 1a and R 1b are independently selected from:
  • R 2 and R 3 are independently selected from: H; unsubstituted or
  • substituted group is substituted with one or more of:
  • R 2 and R 3 are attached to the same C atom and are combined to form (CH 2 ) u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 1 0 )- ;
  • R 4 and R 5 are independently selected from H and CH 3 ; and any two of R 2 , R 3 , R 4 and R 5 are optionally attached to the same carbon atom;
  • R 6 , R 7 and R 7a are independently selected from: H; C 1 -4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 6 and R 7 may be joined in a ring;
  • R 7 and R 7a may be joined in a ring
  • R 8 is independently selected from:
  • 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
  • heterocycle C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NH-, CN, H 2 N-C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , orR 10 OC(O)NH-;
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl;
  • V is selected from:
  • V is not hydrogen if A 1 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 a heterocycle
  • Y is aryl, heterocycle, unsubstituted or substituted with one or
  • 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;
  • s is 0 or 1 ;
  • t is 0 or 1 ;
  • R 1 a , R 1 b , R 10 , R 1 1 , m, R 2 , R 3 , R 6 , R 7 , p, R 7a , u, R 8 , A 1 , K 2 , V, W, X, n, p, r, s, t and u are as defined above with respect to formula (Il-a);
  • R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom;
  • R 9 is selected from:
  • R 1 a , R 1 b , R 10 , R 1 1 , m, R 2 , R 3 , R 6 , R 7 , p, u, R 7a , R 8 , A 1 , A 2 , V, W, X, n, r and t are as defined above with respect to formula (Il-a);
  • R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom;
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl
  • R 11 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R 1a and R 1b are independently selected from:
  • heterocyclyl 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 -, CN,
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and-N(COR 10 )-;
  • R 7a is selected from
  • R 7b is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl, and
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl;
  • R 8 is independently selected from:
  • 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 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • Z is independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; with respect to formula (Il-e):
  • R 11 , W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R 1a and R 1b are independently selected from:
  • heterocyclyl 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 -, CN,
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and-N(COR 10 )-; R 6 is
  • R 7 a is selected from
  • R 7 b is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 1 0 cycloalkyl, and
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl;
  • R 8 is independently selected from:
  • 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 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl
  • Z is independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; with respect to formula (II -f):
  • R 11 , V, W, m, n, p and r are as defined above with respect to formula (II-a);
  • R 1a and R 1b are independently selected from:
  • heterocyclyl 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 -, CN,
  • R 2a and R 2 b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 7a is selected from
  • R 7b is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl, and
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl;
  • R 8 is independently selected from:
  • 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 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl
  • Z is independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; with respect to formula (Il-g):
  • R 11 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a); R 1a and R 1b are independently selected from:
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 7a is selected from
  • R 7b is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl, and
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl;
  • R 8 is independently selected from:
  • R 11 S(O) m -, R 1 0 C(O)NR 1 0 -, CN, NO 2 , R 1 0 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl
  • Z is independently H 2 or O; q is 0, 1 or 2;
  • u is 0 or 1 ;
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ;
  • R 2 or R 3 are combined with R 6 to form a ring such that R 4 a, R 4b , R 7 a and R 4b are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • R 1 a , R 1 b , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R 2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid,
  • R 2 and R 3 are combined to form - (CH 2 ) s - ; or R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to fo ⁇ n - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 12 is
  • R 13 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from C 1 -C 6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a); R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2)s - ; or
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • 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 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; with respect to formula (Il-k):
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 ,V, W, m, n, p, and r are as defined above with respect to formula (Il-a);
  • R 2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid,
  • R 2 and R 3 are combined to form - (CH 2 ) s -;
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1 ;
  • R c is selected from:
  • R 1 is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
  • the side chains of naturally occurring amino acids including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
  • R 4 is hydrogen or an alkyl group, wherein the alkyl group
  • R 5 is selected from:
  • substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and
  • R 6 is a substituted or unsubstituted aliphatic, aromatic or
  • heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;
  • T is 0 or S(O) m ;
  • n 0, 1 or 2;
  • n 0, 1 or 2; and the pharmaceutically acceptable salts and disulfides thereof.
  • Examples of compounds that selectively inhibit geranylgeranyl-protein transferase-type I include the following: N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine (Compound
  • Examples of compounds which selectively inhibit farnesyl protein transferase include the following:
  • Disulphide of 2(S)-[ 2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)- methyl]pentyloxy-3-phenylpropionyI-homoserine Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino- 3(S)methyl]pentyloxy-3-methylbutanoyl-methionine methyl ester and the pharmaceutically acceptable salts, disulfides or optical isomers thereof.
  • alkyl refers to a monovalent alkane
  • hydrocarbon (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
  • substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
  • Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, and intermpted by from 1 -4 heteroatoms selected from O, S and N.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non- aromatic (non-resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include vinyl, allyl,
  • alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present. Preferred alkynyl groups
  • alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted as defined below.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • 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. Examples of aryl groups include phenyl, naphthyl,
  • anthracenyl biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom,
  • heteroaryl group is optionally substituted with up to three groups.
  • Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms.
  • this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.
  • partially aromatic groups are tetrahydro- imidazo[4,5-clpyridine, phthalidyl and saccharinyl, as defined below.
  • heterocycle or heterocyclic represents a stable 5- to 7- membered monocyclic or stable 8- to 1 1 -membered bicyclic or stable 1 1 -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,
  • heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl, piperidyl, pyridyl and pyrrolidinyl.
  • 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 alkyI)S(O) m -, (C 1 -C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, (C 1 -C 6 alkyl)C(O)-, (C 1 -C 6 alkyl)OC(O)-, N 3 ,(Cl -C 6 alkyl)
  • amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
  • the compounds used in the present method 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.
  • named amino acids are understood to have the natural "L" stereoconfiguration
  • cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring.
  • a cyclic amine moiety include, but are not limited to, the following specific structures:
  • substitution on the cyclic amine moiety by R 2a and R 2b may be on different carbon atoms or on the same carbon atom.
  • cyclic moieties When R 3 and R 4 are combined to form - (CH 2 ) s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R 5a and R 5b are combined to form - (CH 2 ) s -, cyclic moieties as described hereinabove for R 3 and R 4 are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
  • 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
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic,
  • any substituent or variable e.g., R 10 , Z, n, etc.
  • -N(R 1 0 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc.
  • 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 formulas (Il-a) through (Il-k) can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below.

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Abstract

Méthode de traitement anticancéreux consistant à administrer à un patient mammifère une dose efficace d'une combinaison composée d'un inhibiteur de géranylgéranyle-protéine transférase-tpye I et un inhibiteur de farnésyle protéine transférase. L'invention porte en outre sur une méthode de traitement du cancer consistant à administrer à un patient mammifère une dose efficace d'une combinaison d'un inhibiteur sélectif de géranylgéranyle-protéine transférase-type I et d'un inhibiteur sélectif de farnésyle protéine transférase.
PCT/US1997/006248 1996-04-18 1997-04-15 Methode de traitement de cancer WO1997038664A2 (fr)

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AU28022/97A AU2802297A (en) 1996-04-18 1997-04-15 A method of treating cancer
JP09537313A JP2000513711A (ja) 1996-04-18 1997-04-15 癌の治療法

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EP0952842A2 (fr) 1999-11-03

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