WO2000016778A1 - Procede de traitement du cancer - Google Patents
Procede de traitement du cancer Download PDFInfo
- Publication number
- WO2000016778A1 WO2000016778A1 PCT/US1999/021773 US9921773W WO0016778A1 WO 2000016778 A1 WO2000016778 A1 WO 2000016778A1 US 9921773 W US9921773 W US 9921773W WO 0016778 A1 WO0016778 A1 WO 0016778A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- farnesyl
- inhibitor
- protein transferase
- protein
- substituted
- Prior art date
Links
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- 229960001099 trimetrexate Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
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- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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Classifications
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
Definitions
- the present invention relates to methods of treating cancer which comprise administering to a patient in need thereof a combination of an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and an inhibitor of farnesyl-protein transferase.
- HMG-CoA reductase 3-hydroxy-3-methylglutaryl-CoA reductase
- farnesyl-protein transferase an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase
- Chemotherapy the systematic administration of antineoplastic agents that travel throughout the body via the blood circulatory system, along with and often in conjunction with surgery and radiation treatment, has for years been widely utilized in the treatment of a wide variety of cancers.
- the available chemotherapeutic drugs often fail patients because they kill many healthy cells and thus bring on serious side effects that limit the doses physicians can administer.
- Prenylation of proteins by prenyl-protein transferases represents a class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C. (1990), Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990), FASEB J. 4, 3319-3328). This modification typically is required for the membrane localization and function of these proteins.
- Prenylated proteins share characteristic C-terminal sequences including CAAX (C, Cys; A, an 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. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxy methylation follows prenylation of proteins terminating with a XXCC motif (Clarke, S. (1992), Annu. Rev. Biochem. 61, 355- 386). For all of the prenylated proteins, addition of the isoprenoid is the first step and is required for the subsequent steps (Cox, A. D. and Der, C. J. (1992a), Critical Rev. Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) Current Opinion Cell Biol. 4:1008-1016).
- GGPTase farnesyl-protein transferase
- GGPTase-I geranylgeranyl- protein transferase type I
- GGPTase-II geranylgeranyl-protein transferase type-II
- FPTase farnesylates CAAX-containing proteins that end with Ser, Met, Cys, Gin or Ala.
- CAAX tetra- peptides comprise the minimum region required for interaction of the protein substrate with the enzyme.
- 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., O'Hara, M. B., Garsky, V. M., Marshall, M. S., Pompliano, D. L., and Gibbs, J. B., J. Biol. Chem., 266:17438 (1991), U.S. Pat. No. 5,470,832).
- the prenylation reactions have been shown genetically to be essential for the function of a variety of proteins (Clarke, 1992; Cox and Der, 1992a; Gibbs, J. B. (1991). Cell 65: 1-4; Newman and Magee, 1993; Schafer and Rine, 1992). This requirement often is demonstrated by mutating the CAAX Cys acceptors so that the proteins can no longer be prenylated. The resulting proteins are devoid of their central biological activity. These studies provide a genetic "proof of principle" indicating that inhibitors of prenylation can alter the physiological responses regulated by prenylated proteins.
- the Ras protein is part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- 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 272:810-812).
- 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, 249:1133-1139 (1990); Manne 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-Aaa-Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 320:583-586 (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 Cl5 or C20 isoprenoid, respectively.
- farnesylated proteins include the Ras-related GTP- binding proteins such as RhoB, 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 farnesylated proteins of unknown structure and function in addition to those listed above.
- 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-r ⁇ s H-r ⁇ s
- N-r ⁇ s N-r ⁇ s
- K4A-r ⁇ s K4B-ras respectively.
- H-r ⁇ s is an abbreviation for Harvey-ras.
- K4A-r ⁇ s and K4B-ras are abbreviations for the Kirsten splice variants of ras that contain the 4A and 4B exons, respectively.
- lovastatin inhibition of cell growth in vitro by lovastatin is not specific to cells transformed by mutated Ras proteins (DeClue, J.E. et al., Cancer Research, 51:712-717 (1991)). It has also been observed that concentrations of lovastatin which inhibit 50% of sterol biosynthesis in vitro show no inhibitory activity against protein prenylation (Sinensky, M. et al. J. Biol. Chem.265: 19937 (1990)). It has been disclosed that the lysine-rich region and terminal CVIM sequence of the C-terminus of K4B-Ras confer resistance to inhibition of the cellular processing of that protein by certain selective FPTase inhibitors. (James, et al., J.
- d-Limonene is described as an inhibitor of protein-farnesyl transferase in JP 07-316076, but the same group of scientists contemporaneously states that it has not been directly demonstrated that the compound is an inhibitor of farnesyl- protein transferase (British J. Cancer, 69:1015-1020 (1994)).
- d-limonene is a "weak inhibitor" of farnesyl-protein transferase (eg., M. H. Gelb et al. Cancer Letters 91:169-175 (1991); K. R. Stayrook et al. Anticancer Researchl8:823-828 (1998)).
- compositions that comprise compounds which are dual inhibitors of squalene synthetase and protein farnesyl- transferase and compounds which are HMG-CoA reductase inhibitor have been generally described (PCT Publs. WO 96/33159 and WO 96/34850).
- a method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a therapeutic composition that comprises a first compound which is an HMG-CoA reductase inhibitor, and a second compound which is an inhibitor of farnesyl-protein transferase.
- FIGURE 1 Western Analysis SDS-PAGE Electrophoresis ofPSN-1 cell lysates:
- the figure shows an X-ray film that was exposed to a PVDF membrane following transfer from a SDS-PAGE electrophoresis gel.
- the Western blot was developed with Kirsten-ras specific monoclonal antibody, c-K-ras Ab-1 (Calbiochem).
- the proteins were isolated from the lysates of PSN-1 cells that had been exposed to vehicle (lane 1), 3 ⁇ M Compound 2 (Example 12 ) in the presence or absence of simvastatin as shown (lanes 2-4), 3 ⁇ M Compound 1 (Example 2) in the presence or absence of simvastatin as shown (lanes 5-7) and 3 ⁇ M Compound 3 (Example 16A) in the presence or absence of simvastatin as shown (lanes 8-10). Details of the assay procedure can be found in Example 24.
- the present invention relates to a method of treating cancer which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a therapeutic composition that comprises a first compound which is an HMG-CoA reductase inhibitor, and a second compound which is an inhibitor of farnesyl-protein transferase.
- a therapeutic composition that comprises a first compound which is an HMG-CoA reductase inhibitor, and a second compound which is an inhibitor of farnesyl-protein transferase.
- the present method of treating cancer by simultaneously inhibiting an enzyme which catalyzes the farnesylation of the cysteine residue of the CAAX motif and inhibiting production of polyisoprenoids including geranylgeranyl pyrophosphate offers advantages over previously disclosed methods which utilize a farnesyl-protein transferase inhibitor alone, in that the dosage of the inhibitor of farnesyl- protein transferase can be reduced.
- any compounds which act as an HMG-CoA reductase inhibitor and any compounds which inhibit farnesyl-protein transferase can be used in the instant method. It is preferred that the inhibitor of farnesyl-protein transferase is a selective inhibitor of farnesyl-protein transferase.
- the HMG-CoA reductase inhibitor and the inhibitor of farnesyl-protein transferase may be administered either sequentially in any order or simultaneously.
- administration of the HMG-CoA reductase inhibitor from one to several days prior to administration of the inhibitor of farnesyl -protein transferase may be advantageous.
- the therapeutic effect of the instant compositions may be achieved with smaller amounts of the farnesyl- protein transferase inhibitor than would be required if such a farnesyl- protein transferase inhibitor was administered alone, thereby avoiding adverse toxicity effects which might result from administration of an amount of the farnesyl-protein transferase inhibitor sufficient to achieve the same therapeutic effect.
- the therapeutic effect of the instant compositions may be achieved with amounts of an inhibitor of HMG-CoA reductase that are known to be tolerated in man (see Thibault, A., Proc. Am. Assoc. Cancer Res., Vol. 35, Abstract 1351 (1994)). It is also anticipated that the instant compositions will achieve a synergistic therapeutic effect or will exhibit unexpected therapeutic advantage over the effect of any of the component compounds if administered alone.
- prenyl-protein transferase inhibiting compound refers to compounds which antagonize, inhibit or counteract the expression of the gene coding a prenyl-protein transferase or the activity of the protein product thereof.
- farnesyl protein transferase inhibitor and inhibitor of farnesyl-protein transferase likewise refers to compounds which antagonize, inhibit or counteract the expression of the gene coding farnesyl-protein transferase or the activity of the protein product thereof.
- the term selective as used herein refers to the inhibitory activity of the particular compound against farnesyl-protein transferase activity.
- the extent of selectivity of the farnesyl-protein transferase inhibitor component of the composition of the instant invention may affect the advantages that the method of treatment claimed herein offers over previously disclosed methods of using a combination of an HMG- CoA reductase inhibitor and compounds which are described as inhibitor of farnesyl-protein transferase.
- use of two independent pharmaceutically active components that have complementary, essentially non-overlapping 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 pharmaceutical activity profile.
- a selective inhibitor of farnesyl-protein transferase exhibits at least 20 times greater activity against farnesyl- protein transferase when comparing its activity against another receptor or enzymatic activity (such as geranylgeranyl-protein transferase type I or squalene synthetase), respectively. More preferably the selectivity is at least 100 times or more.
- the inhibitor of farnesyl-protein transferase is a selective inhibitor of farnesyl-protein transferase and is characterized by: a) an IC Q (a measurement of in vitro inhibitory activity) of less than about 500 nM against transfer of a farnesyl residue to a protein or
- F peptide substrate comprising a CAAX motif by farnesyl-protein transferase.
- the inhibitor of farnesyl-protein transferase is a selective inhibitor of farnesyl-protein transferase and is characterized by: a) an IC Q (a measurement of in vitro inhibitory activity) of less than about 100 nM against transfer of a farnesyl residue to a protein or
- F peptide substrate comprising a CAAX motif by farnesyl-protein transferase.
- the inhibitor of farnesyl-protein transferase is a selective inhibitor of farnesyl-protein transferase and is further characterized by: b) an IC50 (a measure of in vitro inhibitory activity) for inhibition of the prenylation of newly synthesized K-Ras protein more than about 100-fold higher than the IC5Q for the inhibition of the farnesylation of hDJ protein.
- an IC50 a measure of in vitro inhibitory activity
- the selective inhibitor of farnesyl- protein transferase is further characterized by: c) an IC 0 (a measurement of in vitro inhibitory activity) for inhibition of K4B-Ras dependent activation of MAP kinases in cells at least 100-fold greater than the ICQQ for inhibition of the farnesylation of the protein hDJ in cells.
- the selective inhibitor of farnesyl- protein transferase is further characterized by: d) an IC5Q (a measurement of in vitro inhibitory activity) against H- Ras dependent activation of MAP kinases in cells at least 1000 fold lower than the inhibitory activity (IC50) against H-r ⁇ s-CVLL
- the assays described in Example 22 may be utilized. It is preferred that the therapeutic compositions which are efficacious in vivo as an inhibitor of the growth of cancer cells characterized by a mutated K4B-Ras protein utilized in the instant invention are efficacious in vivo in the inhibition of both farnesylation and geranylgeranylation of the K4B-Ras protein.
- such a composition which may be termed a Class II prenyl-protein transferase inhibiting therapeutic composition, is characterized by the following in vitro activity in the assays described in the Examples (Criteria A): a) inhibition of the cellular prenylation of greater than (>) about 50% of the newly synthesized K4B-Ras protein after incubation of assay cells with the composition of the invention.
- assay cells examples include 3T3, C33a, PSN-1 (a human pancreatic carcinoma cell line) and K-r ⁇ s-transformed Rat-1 cells.
- PSN-1 a human pancreatic carcinoma cell line
- K-r ⁇ s-transformed Rat-1 cells Preferred assay cell lines have been found to be PSN-1.
- the preferred newly synthesized protein, whose percentage of processing is assessed in this assay, is selected from K4B-Ras and Rapl.
- the concentration of the instant composition that is tested when evaluating whether the instant therapeutic composition is characterized by Criteria A is a concentration that includes a concentration of less than ( ⁇ ) 5 ⁇ M of the farnesyl-protein transferase inhibitor and a concentration of ⁇ 1 ⁇ M of the HMG-CoA reductase inhibitor.
- a Class II prenyl-protein transferase inhibiting therapeutic composition may also be characterized by (Criteria B): b) inhibition of greater than (>) about 50% of the K4B-Ras dependent activation of MAP kinases in cells. It is preferred that the concentration of the instant composition that is tested when evaluating whether the instant therapeutic composition is characterized by Criteria B is a concentration that includes a concentration of ⁇ 5 ⁇ M of the farnesyl-protein transferase inhibitor and a concentration of ⁇ 1 ⁇ M of the HMG-CoA reductase inhibitor.
- the concentration of the instant composition that is tested for evaluating Criteria B is a concentration that includes a concentration of ⁇ 5 ⁇ M of the farnesyl-protein transferase inhibitor and a concentration of ⁇ 100 nM of the HMG-CoA reductase inhibitor.
- a Class II prenyl-protein transferase inhibiting therapeutic composition may also be characterized by (Criteria C): c) an ICg ⁇ (a measurement of in vitro inhibitory activity) for inhibition of H-Ras dependent activation of MAP kinases in cells at least about 2 fold lower but less than about 20,000 fold lower than the inhibitory activity (IC50) against H-r ⁇ s-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells.
- ICg ⁇ a measurement of in vitro inhibitory activity
- the concentration of the instant composition that is tested when evaluating whether the instant therapeutic composition is characterized by Criteria C is a concentration that includes a concentration of ⁇ 5 ⁇ M of the farnesyl-protein transferase inhibitor and at a concentration of ⁇ 1 ⁇ M of the HMG-CoA reductase inhibitor. More preferably, the concentration of the instant composition that is tested for evaluating Criteria C is a concentration that includes a concentration of ⁇ 5 ⁇ M of the farnesyl-protein transferase inhibitor and at a concentration of ⁇ 100 nM of the HMG- CoA reductase inhibitor.
- assay cells examples include 3T3, C33a, PSN-1 (a human pancreatic carcinoma cell line) and K-r ⁇ s-transformed Rat-1 cells.
- Preferred assay cell lines have been found to be C33a cells.
- Example 22 A method for measuring the activity of the therapeutic composition utilized in the instant methods against Ras dependent activation of MAP kinases in cells is described in Example 22.
- the preferred therapeutic effect provided by the instant composition is the treatment of cancer and specifically the inhibition of cancerous tumor growth and/or the regression of cancerous tumors.
- Cancers which are treatable in accordance with the invention described herein include cancers of the brain, breast, colon, genitourinary tract, prostate, skin, lymphatic system, pancreas, rectum, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma, small cell lung cancers, bladder cancers, head and neck cancers, acute and chronic leukemias, melanomas, and neurological tumors.
- composition of this invention is 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 instant composition to a mammal in need of such treatment.
- the composition is useful in the treatment of neurofibromatosis, which is a benign proliferative disorder.
- composition of the instant invention is 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 composition may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaff er et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal, 2:A3160 (1988)).
- the instant composition may also inhibit tumor angio- genesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)).
- Such anti-angiogenesis properties of the instant composition may also be useful in the treatment of certain forms of vision deficit related to retinal vascularization.
- composition 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 instant composition may also be useful in the inhibition of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies.
- the instant composition may comprise a combination of an inhibitor of farnesyl-protein transferase and an HMG-CoA reductase inhibitor, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, according to standard pharmaceutical practice.
- the composition may be administered to mammals, preferably humans.
- the instant composition can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
- compositions containing the active ingredients may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl- pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a water soluble taste masking material such as hydroxypropylmethyl- cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
- sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
- the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
- the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
- a continuous intravenous delivery device may be utilized.
- An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectable s.
- compositions may also be administered in the form of a suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- creams, ointments, jellies, solutions or suspensions, etc. containing the combination of an inhibitor of farnesyl- protein transferase and an HMG-CoA reductase inhibitor are employed.
- compositions of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
- an inhibitor of farnesyl-protein transferase and an HMG-CoA reductase inhibitor of the instant method 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 combination may be useful in further combination with known anti- cancer and cytotoxic agents.
- the instant combination may be useful in further combination with agents that are effective in the treatment and prevention of neurofibromatosis, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
- an inhibitor of farnesyl-protein transferase and an HMG-CoA reductase inhibitor may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- the instant combination of an inhibitor of farnesyl- protein transferase and an HMG-CoA reductase inhibitor may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity.
- the instant combination of an inhibitor of farnesyl-protein transferase and an HMG-CoA reductase inhibitor may also be co-administered with compounds that are selective inhibitors of geranylgeranyl protein transferase or dual inhibitors of farnesyl- protein transferase and geranylgeranyl-protein transferase.
- composition of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant farnesyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that the instant combination of a combination of an inhibitor of farnesyl- protein transferase and an HMG-CoA reductase inhibitor may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
- 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.
- Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with a combination of an inhibitor of farnesyl-protein transferase and an HMG-CoA reductase inhibitor.
- compositions of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on October 23, 1997, and herein incorporated by reference.
- the composition of the instant invention may be administered to a patient in need prior to the application of radiation therapy.
- an HMG-CoA reductase inhibitor is administered prior to the administration of an inhibitor of farnesyl-protein transferase, and administration of radiation therapy is either at the same time as administration of the inhibitor of farnesyl-protein transferase or after the administration of the inhibitor of farnesyl-protein transferase.
- the instant composition may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed April 6, 1998, which is incorporated herein by reference.
- an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells.
- the term refers to compounds which selectively 5 antagonize, inhibit or counteract binding of a physiological ligand to the v ⁇ 3 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the v ⁇ 3 integrin and the ⁇ v ⁇ integrin, or which antagonize, inhibit or
- the term 10 counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
- the term also refers to antagonists of the ⁇ v ⁇ 6, ⁇ v ⁇ 8, ⁇ l ⁇ l, ⁇ 2 ⁇ l, ⁇ l, ⁇ 6 ⁇ l and ⁇ 6 ⁇ 4 integrins.
- the term also refers to antagonists of any combination of ⁇ v ⁇ 3, ⁇ v ⁇ , ⁇ v ⁇ 6, ⁇ v ⁇ 8, ⁇ l ⁇ l, ⁇ 2 ⁇ l, ⁇ l, ⁇ 6 ⁇ l and ⁇ 6 ⁇ 4 integrins.
- the instant compounds may also l ⁇ be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin.
- composition according to this invention When a composition according to this invention is administered into a human subject, the daily dosage will normally be
- the dosage 20 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.
- 2 ⁇ CoA reductase 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.
- a particular daily therapeutic 0 dosage that comprises the instant composition includes from about 10 mg to about 3000mg of a farnesyl-protein transferase inhibitor and about O.lmg to about 3000mg of an HMG-CoA reductase inhibitor.
- the daily dosage comprises from about lOmg to about lOOOmg of a farnesyl-protein transferase inhibitor and about 0.3mg to about 160mg 5 of an HMG-CoA reductase inhibitor.
- an antineoplastic agent include, in general, microtubule-stabilising agents (such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), or their derivatives); alkylating agents, anti-metabolites; epidophyllotoxin; ⁇ an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
- Example classes of antineoplastic agents include, for 0 example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
- Particularly useful members of those classes include, for example, doxorubicin, carminomycin, 5 daunorubicin, aminopterin, methotrexate, methopterin, dichloro- methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, 0 vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
- antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, ⁇ topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
- HMG-CoA reductase inhibitor and "inhibitor of HMG-CoA reductase” have the same meaning when used herein.
- HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACOR®; see US Patent No. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR®; see US Patent No. 4,444,784; 4,820,8 ⁇ 0; 4,916,239), pravastatin (PRAVACHOL®; see US Patent Nos. 4,346,227; 4, ⁇ 37,8 ⁇ 9; 4,410,629; ⁇ ,030,447 and 5,180,589), fluvastatin (LESCOL®; see US Patent Nos.
- HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open- acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
- An illustration of the lactone portion and its corresponding open-acid form is shown below as structures I and II.
- HMG-CoA reductase inhibitor In HMG-CoA reductase inhibitor's where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
- the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
- the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as ⁇ sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, orni thine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
- HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, l ⁇ chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactob
- 2 ⁇ inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
- Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, R S(0) m -, R 1 0C(O)NR 1 0-, CN, NO2, (R 10 )2N-C(NR 1( >)-, RlOC(O)-, R 10 OC(O)-, N3, ⁇ -N(R!0)2, or RllOCXCONRlO-, c) Ci-C ⁇ alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 O-, RllS(0) m -, R 10 C(0)NR!0-, CN, (R 10 )2N-C(NR 1 0)-, R10C(O)-
- R2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or l ⁇ substituted heterocycle,
- substituted group is substituted with one or more of: 20 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl,
- R2 and R ⁇ are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ; R4 and R ⁇ are independently selected from H and CH3; and any two of
- R2, R3, R4 and R ⁇ are optionally attached to the same carbon atom;
- R 6 , R' 7 and R' ?a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, ⁇ heteroarylsulfonyl, unsubstituted or substituted with:
- R 6 and R' 7 may be joined in a ring
- R ' and R ⁇ a ma y be joined in a ring
- R8 is independently selected from:
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 11 S(0) m -, R 1 0c(O)NR 10 -, CN, NO2, (R!0)2N-C-(NR 1 0)-, RlOC(O)-, R 10 OC(O)-, N3, -N(R 10 )2, or R 1 l ⁇ C(0)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, R n S(0)m-, R 10 C(O)NR 10 -, CN, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, RlO ⁇ C(O)-, N3, -N(R 10 )2, or RHOC(0)NR 10
- RlO i s independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
- RU is independently selected from Cl-C ⁇ alkyl and aryl; l ⁇
- 20 V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced
- V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if A* is a bond, n is 0 and A2 is S(0) m ;
- Y is aryl, heterocycle, unsubstituted or substituted with one or ⁇ more of: 1) Cl-4 alkyl, unsubstituted or substituted with a) Cl-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 6 , or g) -C(0)NR6R7,
- R4 is selected from H and CH3;
- R2, R3 and R ⁇ are optionally attached to the same carbon 10 atom;
- R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RiOO-, l ⁇ R 11 S(0)m-, R 10 C(O)NR 1 0-, CN, NO2,
- G is H2 or O
- ⁇ Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
- Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 6 , or g) -C(0)NR 6 R 7 ,
- R4 is selected from H and CH3; and any two of R , R3 and R ⁇ are optionally attached to the same carbon atom; G is O;
- Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, ⁇ arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
- Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6 R 7 ,
- Y is a ⁇ , 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom;
- Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, R n S(0) m -, R 10 C(O)NR 10 -, RHC(0)0-, (R 10 )2NC(O)-, R 1 0 2 N-C(NR 10 )-, CN, NO2, 0 RIOC(O)-, N3, -N(RlO)2, or RllOC ⁇ NRi -, c) unsubstituted or substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RllS(0) m -, Rl
- R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl2 ⁇ -,
- Rl0 2 N-C(NR 10 )-, CN, N02, R 10 C(O)-, N3, -N(R 10 )2, or
- RllOC(0)NR 10 - c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the l ⁇ substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl2 ⁇ -, RllS(0)m-, R 10 C(O)NR 1 0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(RlO)2, and 20 RHOC(0)-NR 10 -;
- R6a ; R6b 6C ; R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 2 ⁇ substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl2 ⁇ -, RllS(0) m -, R 10 C(O)NR 1 0-, (RlO) 2 NC(0)-, R11S(O)2NR10-, (Rl0) 2 NS(O)2-, R n C(0)0-, Rl0 N-C(NR 10 )-, CN, N02, R 10 C(O)-, N3, -N(R 10 )2, or
- Rl 1 OC(0)NR 10 - c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl2 ⁇ -, R 11 S(0) m -, R!0C(O)NR 10 -, (R 10 )2NC(O)-, R 11 S(O)2NR 1 0-, (Rl0) 2 NS(O)2-, R 10 2N-C(NR 10 )-, CN, R10 ( XO)-, N3, -N(R!0)2, and R OC(0)-NR 10 -; or ⁇ any two of R 6a , R D , R 6 C ?
- R 7 is selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle,
- R8 is independently selected from: 20 a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R S(0) m -, R 10 C(O)NRl0- (RlO) 2 NC(0)-, R 1 lS(0)2NRlO- ; (Rl0) 2 NS(O)2-, ⁇ Rl0 N-C(NR 1 0)-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or
- R 11 OC(0)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RiOO-, 0 RllSCC m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 11 S(O)2NR 1 0-,
- R9 is independently selected from: a) hydrogen, ⁇ b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br,
- RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2- l ⁇ trifluoroethyl and aryl;
- RU is independently selected from Cl-C ⁇ alkyl and aryl
- Rl2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, 20 C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
- Rl3 i selected from hydrogen, Cl-C ⁇ alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl;
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, ⁇ provided that V is not hydrogen if A ⁇ is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A is S(0) m ;
- W is a heterocycle
- Rl, R2, R3, R4 ; R ⁇ , R 6a-e, R7, RS, R9, R10, RU R12 ; R13, A l, A 2, V , W, m, n, p, q, r and t are as previously defined with respect to formula (II);
- Y is a ⁇ , 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom; l ⁇
- Rla, Rib, Rlc an( j Rid are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RHS(0) m -, R 1 0c(O)NR 1 0-, (RlO) 2 N-C(0)-, CN, NO2, (R 10 )2N-C(NR 1 0)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(R! )2, or Rl 1 OC(0)NR 10 -, c) unsubstituted or substituted Cl-C ⁇ alkyl wherein the
- 10 substitutent on the substituted C1-C alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, R 11 S(0) m -, RlOC(0)NRlO-, (RlO) 2 N-C(0)-, CN, (R10) 2 N-C(NR!0)-, R!0C(O)-, R!0 ⁇ C(O)-, N3, -N(R 10 ) 2 , and R 11 OC(O)-NRl0- ; l ⁇
- R2 ? R b ; R3a an( j R3b are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
- substituted group is substituted with one or more of:
- R2 and R are attached to the same C atom and are combined to form ⁇ - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
- R2 and R are optionally attached to the same carbon atom
- R4 is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, l ⁇ d) HO,
- R 5 , R 6 and R 7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
- R 6 and R 7 may be joined in a ring; and independently, R5 and R 7 may be joined in a ring;
- R8 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, l ⁇ C -C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 11 S(0) m -,
- ⁇ R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R S(0) m -, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, R 1 0 2 N-C(NRlO)-, CN, NO2, R 10 C(O)-, R 10 OC(O)-, N3, 0 -N(R!0)2, or RH ⁇ C(O)NR 1 0-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 O-, RUS(0) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 1 0 2 N-C(NR 10 )-, CN, R 10 C(O)-, R 10 OC(O)-, N3,
- RIO is independently selected from hydrogen, Cl-C ⁇ alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
- 10 RU is independently selected from Cl-C ⁇ alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
- a 1 is selected from: a bond, -C(O)-, -C(0)NR 10 -, -NR 10 C(O)-, O, -N(RlO)-, -S(0)2N(RlO)-, -N(Rl )S(0) 2 -, and S(0) m ; l ⁇
- A2 is selected from: a bond, -C(O)-, -C(0)NR 10 -, -NRlOC(O)-, O, -N(RlO)-, -S(0)2N(RlO)-, -N(RlO)S(0)2-, S(0) m and -C(Rld) 2 -;
- G and G3 a re independently selected from: H2 and O;
- W is heterocycle
- V is selected from: 2 ⁇ a) heterocycle, and b) aryl;
- Zl is selected from: unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR R 7 , c) C3-6 cycloalkyl, ⁇ d) aryl or heterocycle, e) HO, f ) -S(0)mR 4 , or g) -C(0)NR 6 R 7 ,
- 20 Z2 is selected from: a bond, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
- n 0,1 or ⁇ 2;
- Rid an( j Rle are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIOQ-, R 11 S(0) m -, R 10 C(O)NR 10 -, (RlO) 2 N-C(0)-, CN, N02, (R 10 )2N-C(NRl )-, R10C(O)-, RlO ⁇ C(O)-, N3, -N(R!0)2, or RHOC(O)NR10-, c) unsubstituted or substituted Cl-C ⁇ alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from ⁇ unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -
- R3a anc ⁇ R3b are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C 2 -8 alkenyl, unsubstituted or substituted C 2 -8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
- substituted group is substituted with one or more of:
- R2 and R3 are attached to the same C atom and are combined to form - (CH2)u ⁇ wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N CORi )- ;
- R2 and R a re optionally attached to the same carbon atom
- R 4 is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
- R5, R 6 and R 7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
- R 6 and R 7 may be joined in a ring; and independently, R5 and R 7 may be joined in a ring;
- R8 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C ⁇ alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R S(0)m-, R10C(O)NR10_, (RlO) 2 NC(0)-, R 1 0 2 N-C(NR 1 0)-, CN, N02, R!0C(O)-, RlOoC(O)-, N3, -N(R!0)2, or R 11 OC(0)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C -C ⁇ alkenyl, C 2 -
- R9 is selected from: a) hydrogen, b) C 2 -C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(0) m -, R 10 C(O)NRl0-, (RlO) 2 NC(0)-,
- R J -0 is independently selected from hydrogen, C1-C6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
- Rl! is independently selected from Cl-C ⁇ alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
- Al is selected from: a bond, -C(O)-, -C(O)NRl0-, -NRlO( ⁇ )-, O, -N(R!0)-, -S(0) 2 N(RiO)-, -N(R!0)S(O)2-, and S(0) m ;
- A2 is selected from: a bond, -C(O)-, -C(O)NRl0-, -NRIOC(O)-, O, ⁇ -N(R!0)-, -S(O)2N(R!0)-, -N(RlO)S(0)2-, S(0) m and
- W is heteroaryl
- 10 V is selected from: a) heteroaryl, and b) aryl;
- X is selected from: -C(O)-, -C(O)NR 1 0-, -NR10C(O)-, -NRl0C(O)-O-, l ⁇ -O-C(O)NRl0-, - NR!0C(O)NR 10 -, - C(O)NRl0C(O)-, O, -N(RiO)-, -S(0) 2 N(RlO)-, -N(RlO)S(0) 2 - and S(0) m ;
- Zl is selected from: unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or 20 substituted heteroaryl is substituted with one or more of: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6 R 7 ,
- Z2 is selected from: a bond, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted
- Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6 R 7 , l ⁇ c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 4 , or g) -C(0)NR 6 R 7 ,
- R and Rib are independently selected from: 10 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Rl O-, RHS(0) m -, R 10 C(O)NR 1 0-, (Rl°) 2 N-C(0)-, CN, N0 2 , (RlO) 2 N-C(NRlO)-, R10C(O)-, N3, -N(RlO) 2 , or RllOC(O)NRl0-, l ⁇ c) unsubstituted or substituted Cl-C ⁇ alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C 2 -C ⁇ alkenyl, C -C ⁇ alkynyl, RlOO-, RHS(0)
- Rlc is selected from: a) hydrogen, b) unsubstituted or substituted Cl-C ⁇ alkyl wherein the ⁇ substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C ⁇ alkynyl, Rl O-, RHS(0) m -, Rl0c(O)NRl0-, (RlO) 2 N-C(0)-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , and RHOC(0)-NR10-, and c) unsubstituted or substituted aryl;
- R2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C 2 -8 alkenyl, unsubstituted or substituted C 2 -8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, ORlO,
- aryl or heterocycle unsubstituted or substituted with: a) Cl-4 alkyl, b) (CH 2 ) p OR 6 , c) (CH 2 ) p NR R 7 , l ⁇ d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl-4 alkyl, h) SR 6a , S(0)R 6a , S0 2 R 6a
- R and R 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(0) m , -NC(O)-, and -N(COR 10 )- ;
- R 4 and R ⁇ are independently selected from H and CH3;
- R 6 , R 7 and R 7a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, ⁇ b) unsubstituted aryl, substituted aryl, unsubstituted heteroaryl or substituted heterocycle, c) halogen, d) HO,
- R 6 and R 7 may be joined in a ring;
- R 7 and R 7a may be joined in a ring;
- R 6a is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, 20 d) HO,
- R8 is independently selected from: ⁇ a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, C 2 -C ⁇ alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, RlOC(0)NRlO-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, NO 2 , RlOC(O)-, N3, -N(Rl ) 2 , or RHOC(0)NR1 -, and c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C 2 -C6 alkenyl, ⁇ C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl°0-, RHS(0) m -,
- R9 is selected from: 10 a) hydrogen, b) C 2 -C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0)m-, R 10 C(O)NR 10 -, (Rl°)2NC(0)-, Rl0 2 N-C(NRlO)-, CN, NO2, Rl°C(0)-, N3, -N(Rl°) 2 , or
- RlO is independently selected from hydrogen, C1-C14 alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted aryl;
- RU is independently selected from Cl-C ⁇ alkyl and substituted or ⁇ unsubstituted aryl;
- Rl2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, 0 wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of:
- aryl or heterocycle unsubstituted or substituted with: a) Cl-4 alkyl, b) (CH ) p OR 6 , c) (CH 2 ) p NR 6 R 7 , d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl-4 alkyl, h) SR 6a , S(0)R 6a , S0 2 R 6a ,
- V is selected from: a) hydrogen, b) heterocycle, 10 c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if l ⁇ Al is a bond, n is 0 and A 2 is S(0) m ;
- W is a heterocycle
- Y is selected from: a) hydrogen, b) Rl O-, RllS(0) m -, RlOC(0)NRlO-, (RlO) 2 N-C(0)-, CN, N02, (RlO) 2 N-C(NRl )-, R12C(0)-, RlO ⁇ C(O)-, N3, F, -N(RlO)2, or RllOC(O)NRl0-, and c) unsubstituted or substituted Cl-C6 alkyl wherein the substitutent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, RlOO-, R1°C(0)NR10-, (RlO) 2 N-C(0)-, RlOC(O)- and RlOoC(O)-;
- Z is an unsubstituted or substituted group selected from aryl
- Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR 6 R 7 , l ⁇ c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(0) m R 6a , or g) -C(0)NR 6 R 7 ,
- Rla, Rib an d RI C are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, l ⁇ C2-C6 alkynyl, R ⁇ O-, R 9 S(0) m -, R 8 C(0)NR 8 -, CN, NO2,
- R is selected from: H; unsubstituted or substituted Cl-8 alkyl, ⁇ unsubstituted or substituted C -8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, in the substituted group is substituted with one or more of:
- R 4 is independently selected from: 10 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 0-, R9S(0) m -, R8C(0)NR8-, CN, NO2, R 8 2N-C(NR8)-, R 8 C(0)-, R 8 OC(0)-, l ⁇ N3, -N(R 8 )2, or R90C(0)NR 8 -, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 0-, R9S(0) m -, R8C(0)NH-
- R5 is independently selected from: a) hydrogen, b) C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 0 perfluoroalkyl, F, Cl, Br, R80-, R9S(0) m -, R 8 C(0)NR 8 -, CN,
- R 6 , R 7 and R 7a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or 0 substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, 5 d) HO,
- R 6 and R 7 may be joined in a ring;
- R 7 and R 7a may be joined in a ring;
- R8 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl;
- R9 is independently selected from Cl-C6 alkyl and aryl
- RIO is selected from: H; R8C(0)-; R9S(0)m-; unsubstituted or substituted Cl-4 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted arylsulfonyl, l ⁇ unsubstituted or substituted heteroarylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, 20 d) HO,
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C 2 o alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0)rn;
- W is a heterocycle
- n 0, 1, 2, 3 or 4;
- P is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0 to ⁇ , provided that r is 0 when V is hydrogen; s is l or 2; t is 0 or 1; and
- inhibitors of farnesyl-protein transferase are illustrated by the formula I-b':
- Rla is selected from: hydrogen or Cl-C ⁇ alkyl
- Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R1°) or C -C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO) ;
- R3 and R 4 selected from H and CH3;
- R2 is selected fromH; unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
- O or Cl-5 alkyl unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle,
- R 6 and R 7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, ⁇ c) perfluoro-Cl-4 alkyl, or d) aryl or heterocycle;
- R a is selected from:
- R 8 is independently selected from: a) hydrogen, b) Cl-C ⁇ alkyl, C 2 -C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, R 10 O-, Rl0C(O)NRl0-, CN, NO2, (RlO) 2 N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or RHOC(0)NR 10 -,
- RlO is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- 0 RU is independently selected from Cl-C ⁇ alkyl and aryl
- Al and A a re independently selected from: a bond, -CH CH-, -C ⁇ C-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ;
- V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, ⁇ quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C 2 0 alkenyl, and
- V is not hydrogen if Al is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0) m ;
- l ⁇ Z is selected from:
- a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- n 0, 1, 2, 3 or 4
- p 0, 1, 2, 3 or 4
- l ⁇ r is 0 to ⁇ , provided that r is 0 when V is hydrogen
- inhibitors of farnesyl-protein transferase are illustrated by the formula Il-a:
- f(s) are independently N, and the remaining f s are independently CH;
- ⁇ g is selected from N and CH;
- Rl is selected from: hydrogen, C3-C10 cycloalkyl or Cl-C ⁇ alkyl;
- R2 is independently selected from: 10 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(R10) 2 , F or C 2 -C ⁇ alkenyl, c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C 2 -C ⁇ alkenyl, Rl°0-,
- R8 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, C3-C10 cycloalkyl, C 2 -C ⁇ alkenyl, C 2 -C ⁇ alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl2 ⁇ -, RllS(0) m -, R10C(0)NR10-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, N0 2 , Rl°C(0)-, N3, -N(RlO) 2 , or
- RllOC(O)NRl0- ⁇ c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C 2 -C ⁇ alkenyl, C 2 -C ⁇ alkynyl, 0 Rl2 ⁇ -, RllS(0)m-, R 10 C(O)NRl0-, (Rl ) 2 NC(0)-,
- Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO) 2 , and R110C(0)-NR1°-;
- R 4 is selected from H, halogen, Cl-C ⁇ alkyl and CF3;
- R6a ⁇ R ⁇ b R6d an( j R6e are independently selected from: ⁇ a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C 2 -C ⁇ alkenyl, C 2 -C ⁇ alkynyl, halogen, Cl-C ⁇ perfluoroalkyl, Rl2 ⁇ -, RllS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, 0 Rl0 2 N-C(NRlO)-, CN, NO2, Rl°C(0)-, N3, -N(RlO)2, or
- RllOC(O)NRl0- c) unsubstituted Cl-C ⁇ alkyl, d) substituted Cl-C ⁇ alkyl wherein the substituent on the substituted Cl-C ⁇ alkyl is selected from unsubstituted or 5 substituted aryl, unsubstituted or substituted heterocyclic,
- ⁇ R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C ⁇ alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, Rl°0-, R10C(O)NR1°-, CN, N0 2 , 0 (RlO) 2 N-C(NRlO)-, RlOC(O)-, -N(RlO) 2 , or RHOC(O)NR10-, and c) Cl-C ⁇ alkyl substituted by Cl-C ⁇ perfluoroalkyl, RlOO-, R!0C(O)NR10-, (RlO) 2 N-C(NRlO)-, RIOC(O)-, -N(RlO) 2 , or R11OC(O)NR10- ; ⁇ R9a an d R9o
- RIO is independently selected from hydrogen, Cl-C ⁇ alkyl, amino- Ci-C ⁇ alkyl, N-(unsubstituted or substituted benzolyl)- amino-Ci-C ⁇ alkyl, (Cl-C ⁇ alkyl) 2 -amino-Cl-C ⁇ alkyl, acetylamino-Cl-C ⁇ alkyl, phenyl-Cl-C ⁇ alkyl, 2,2,2- trifluoroethyl, aryl and substituted aryl;
- RU is independently selected from Cl-C ⁇ alkyl and aryl
- Rl2 is independently selected from hydrogen, Cl-C ⁇ alkyl, Cl-C ⁇ aralkyl, Cl-C ⁇ substituted aralkyl, Cl-C ⁇ heteroaralkyl, Cl-C ⁇ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C ⁇ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
- Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
- n is 0 or 1; provided that n is not 0 if A is a bond, O,
- inhibitors of farnesyl-protein transferase are illustrated by the formula IV-a:
- Rla is selected from: hydrogen and Cl-C ⁇ alkyl
- Rib and Rl° is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl O-, -N(RlO) 2 or C 2 -C ⁇ alkenyl, and
- R8a i s selected from H and CH3; R is selected from H; l ⁇
- R 4 is selected from:
- R 6 and R 7 are independently selected from: a) hydrogen, l ⁇ b) Cl-C ⁇ alkyl, C 2 -C ⁇ alkenyl, C 2 -C ⁇ alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, Rl°0-, R!0C(O)NR10-, CN, N0 , (RlO) 2 N-C(NRlO)-, RlOC(O)-, RIOOC(O)-, -N(Rl ) 2 , or RllOC(O)NRl0-, and c) Cl-C ⁇ alkyl substituted by Cl-C ⁇ perfluoroalkyl, Rl O-, 20 Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RIOOC(O)-,
- R8 is independently selected from: a) hydrogen, 25 b) unsubstituted or substituted aryl, Cl-C ⁇ alkyl, C 2 -C ⁇ alkenyl, C 2 -C ⁇ alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, Rl°0-, R!0C(O)NR10-, CN, N0 2 , (Rl ) 2 N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or RllOC(O)NRl0-, and c) Cl-C ⁇ alkyl substituted by unsubstituted or substituted aryl, 0 Cl-C ⁇ perfluoroalkyl, RlOO-, R!0C(O)NR10-,
- R9 is hydrogen or methyl
- RIO is independently selected from hydrogen, Cl-C ⁇ alkyl, benzyl and unsubstituted or substituted aryl
- 5 RU is independently selected from Cl-C ⁇ alkyl and unsubstituted or substituted aryl;
- Al is selected from: a bond, -C(O)- and O;
- Zl is selected from: 5 unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
- n 0, 1, 2, 3 or 4
- ⁇ p 0, 1, 2, 3 or 4
- r is 0 to ⁇
- s is independently 0, 1, 2 or 3;
- alkyl refers to a monovalent alkane
- hydrocarbon (hydrocarbon) derived radical containing from 1 to l ⁇ 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 interrupted 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 l ⁇ 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.
- alkenyl groups examples 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.
- Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
- alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to l ⁇ carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
- Preferred alkynyl groups include ⁇ ethynyl, propynyl and butynyl.
- the straight, branched or cyclic portion of the 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
- aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at
- aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
- heteroaryl refers to a monocyclic aromatic
- the 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, ⁇ -c]pyridine, phthalidyl and saccharinyl, as defined below.
- the term 5 heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11- l ⁇ 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
- heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, l ⁇ benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl
- 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, CF3, NH 2 , N(Ci-C ⁇ alkyl) 2 , N0 2 , CN, (Cl-C ⁇ ⁇ alkyDO-, -OH, (Cl-C ⁇ alkyl)S(0) m -, (Cl-C ⁇ alkyl)C(0)NH-, H2N-C(NH)-, (Cl-C ⁇ alkyl)C(O)-, (Cl-C ⁇ alkyl)OC(O)-, N3,(Ci-C6 alkyl)OC(0)NH- and C1-C20 alkyl.
- 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" stereoconfigur ation .
- R 6a , R D , R 6c , R6d and/or R 6e may be substituted by R 6a , R D , R 6c , R6d and/or R 6e as defined hereinabove.
- Y represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom and includes the following ring systems:
- Y represents a ⁇ -, 6- or 7-membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom and includes the following ring systems:
- fused ring moieties may be further substituted by the remaining R 6a , R 6 ⁇ , R 6c , R 6 d nd/or R 6e as defined hereinabove.
- cyclic moieties are formed.
- examples of such cyclic moieties include, but are not limited to:
- cyclic moieties may optionally include a heteroatom(s).
- 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,
- 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.
- 2 ⁇ Peptidyl compounds that may be useful in the instantly claimed compositions 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.
- compositions are useful in various pharmaceutically acceptable salt forms.
- pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
- Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
- pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
- Non-toxic salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
- 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, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- the pharmaceutically acceptable salts of the compounds useful in the instant invention can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
- the inhibitors of farnesyl-protein transferase of formula (I-b') can be synthesized in accordance with Schemes 1-11, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R, R a and Rb, as shown in the Schemes, represent the substituents R ⁇ , R3, R4 ? an( j R5; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
- Piperazin-5-ones can be prepared as shown in Scheme 1.
- the protected suitably substituted amino acid IV can be converted to the corresponding aldehyde V by first forming the amide and then reducing it with LAH. Reductive animation of Boc-protected amino aldehydes V gives rise to compound VI.
- the intermediate VI can be converted to a piperazinone by acylation with chloroacetyl chloride to give VII, followed by base-induced cyclization to VIII.
- Deprotection, followed by reductive alkylation with a protected imidazole carboxalde- hyde leads to IX, which can be alkylated with an arylmethylhalide to give the imidazolium salt X.
- Final removal of protecting groups by either solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid gives the final product XI.
- the intermediate VIII can be reductively alkylated with a variety of aldehydes, such as XII.
- the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 2).
- the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide.
- the product XIII can be deprotected to give the final compounds XIV with trifluoroacetic acid in methylene chloride.
- the final product XIV is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
- the product diamine XIV can further be selectively protected to obtain XV, which can subsequently be reductively alkylated with a second aldehyde to obtain XVI. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XVII can be accomplished by literature procedures.
- the imidazole acetic acid XVIII can be converted to the acetate XIX by standard procedures, and XIX can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XX (Scheme 3).
- Hydrolysis and reaction with piperazinone VIII in the presence of condensing reagents such as l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXI.
- the piperazinone VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXII in Scheme 4, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 4, 5).
- the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIV.
- the fully deprotected amino alcohol XXV can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXVI (Scheme 5), or tertiary amines.
- the Boc protected amino alcohol XXIII can also be utilized to synthesize 2-aziridinylmethylpiperazinones such as XXVII (Scheme 6).
- the aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXVIII.
- piperazinone VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX (Scheme 7).
- R' is an aryl group
- XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI.
- the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.
- Scheme 8 illustrates the use of an optionally substituted homoserine lactone XXXIII to prepare a Boc-protected piperazinone XXXVII.
- Intermediate XXXVII may be deprotected and reductively alkylated or acylated as illustrated in the previous Schemes.
- the hydroxyl moiety of intermediate XXXVII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate XXXVIII.
- Intermediate XXXVII may also be oxidized to provide the carboxylic acid on intermediate IXL, which can be utilized form an ester or amide moiety.
- N-Aralkyl-piperazin-5-ones can be prepared as shown in
- the imine formed from arylcarboxamides XLII and 2-aminoglycinal diethyl acetal (XLIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine XLIV.
- Amino acids I can be coupled to amines XLIV under standard conditions, and the resulting amide XLV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated XLVI.
- Catalytic hydrogenation under standard conditions gives the requisite intermediate XL VII, which is elaborated to final products as described in Schemes 1-7.
- Amino acids of the general formula IL which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 11 starting with the readily prepared imine XL VIII.
- the protected piperidine intermediate LIII can be deprotected and reductively alkylated with aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or 1-trityl- 4-imidazolylacetaldehyde, to give products such as LVI.
- aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or 1-trityl- 4-imidazolylacetaldehyde
- the trityl protecting group can be removed from LVI to give LVII, or alternatively, LVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole LVIII.
- the deprotected intermediate LIII can also be reductively alkylated with a variety of other aldehydes and acids as shown above in Schemes 4-7.
- Scheme 14 An alternative synthesis of the hydroxymethyl intermediate LIV and utilization of that intermediate in the synthesis of the instant compounds which incorporate the preferred imidazolyl moiety is illustrated in Scheme 14.
- Scheme 15 illustrates the reductive alkylation of intermediate LIV to provide a 4-cyanobenzylimidazolyl substituted piperidine. The cyano moiety may be selectively hydrolyzed with sodium borate to provide the corresponding amido compound of the instant invention.
- Scheme 16 alternative preparation of the methyl ether intermediate LV and the alkylation of LV with a suitably substituted imidazolylmethyl chloride to provide the instant compound. Preparation of the homologous 1 -(imidazolylethyl)piperidine is illustrated in Scheme 17.
- Scheme 20 illustrates the synthesis of the instant compounds wherein the moiety Z is attached directly to the piperidine ring.
- the piperidone LIX is treated with a suitably substituted phenyl Grignard reagent to provide the gem disubstituted piperidine LX.
- Deprotection provides the key intermediate LXI.
- Intermediate LXI may be acetylated as described above to provide the instant compound LXII (Scheme 21).
- the protected piperidine LX may be dehydrated and then hydroborated to provide the 3- hydroxypiperidine LXIII.
- This compound may be deprotected and further derivatized to provide compounds of the instant invention (as shown in Scheme 23) or the hydroxyl group may be alkylated, as shown in Scheme 22, prior to deprotection and further manipulation.
- the dehydration product may also be catalytically reduced to provide the des-hydroxy intermediate LXV, as shown in Scheme 24, which can be processed via the reactions illustrated in the previous Schemes.
- Schemes 25 and 26 illustrate further chemical manipulations of the 4-carboxylic acid functionality to provide instant compounds wherein the substituent Y is an acetylamine or sulfonamide moiety.
- Scheme 27 illustrates incorporation of a nitrile moiety in the 4-position of the piperidine of the compounds of formula II.
- the hydroxyl moiety of a suitably substituted 4-hydroxypiperidine is substituted with nitrile to provide intermediate LXVI, which can undergo reactions previously described in Schemes 17-21.
- Scheme 28 illustrates the preparation of several pyridyl intermediates that may be utilized with the piperidine intermediates such as compound LI in Scheme 16 to provide the instant compounds.
- Scheme 29 shows a generalized reaction sequence which utilizes such pyridyl intermediates.
- Compounds of the instant invention wherein X 1 is a carbonyl moiety may be prepared as shown in Scheme 30.
- Intermediate LXVII may undergo subsequent reactions as illustrated in Schemes 13-17 to provide the instant compounds.
- Preparation of the instant compounds wherein X* is sulfur in its various oxidation states is shown in Scheme 31.
- Intermediates LXVIII-LXXI may undergo the previously described reactions to provide the instant compounds.
- Scheme 32 illustrated preparation of compounds of the formula A wherein Y is hydrogen.
- suitably substituted isonipecotic acid may be treated with N,0-dimethylhydroxylamine and the intermediate LXXII reacted with a suitably substituted phenyl Grignard reagent to provide intermediate LXXIII. That intermediate may undergo the reactions previously described in Schemes 13-17 and may be further modified by reduction of the phenyl ketone to provide the alcohol LXXIV.
- R CH 3 , CH CH 2
- the compounds of the formula (II) are prepared by employing reactions as shown in the Schemes 34-48, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R a and R.b, as shown in the Schemes, represent the substituents R.2, R , R4 ? an d R5; substituent "sub” represents a suitable substituent on the substituent Z.
- the point of attachment of such substituents to a ring is illustrative only and is not meant to be limiting.
- the compounds referred to in the Synopsis of Schemes 34-48 are numbered starting sequentially with 1 and ending with 45.
- Schemes 34-43 illustrate synthesis of the instant bicyclic compounds which incorporate a preferred benzylimidazolyl side chain.
- a bicyclic intermediate that is not commercially available may be synthesized by methods known in the art.
- a suitably substituted pyridinone 1 may be reacted under coupling conditions with a suitably substituted iodobenzyl alcohol to provide the intermediate alcohol 2.
- the intermediate alcohol 2 may converted to the corresponding bromide 3.
- the bromide 3 may be coupled to a suitably substituted benzylimidazolyl 4 to provide, after deprotection, the instant compound 5.
- Schemes 35-37 illustrate methods of synthesizing related or analogous key alcohol intermediates, which can then be processed as described in Scheme 34.
- Scheme 35 illustrates pyridinonyl- pyridyl alcohol forming reactions starting with the suitably substituted iodonicotinate 6.
- Scheme 36 illustrates preparation of the intermediate alcohol 9 wherein the terminal lactam ring is saturated.
- Acylation of a suitably substituted 4-aminobenzyl alcohol 7 with a suitably substituted brominated acyl chloride provides the bisacylated intermediate 8.
- Closure of the lactam ring followed by saponifiaction of the remaining acyl group provides the intermediate alcohol.
- Preparation of the homologous saturated lactam 10 is illustrated in Scheme 37.
- Scheme 38 illustrates the synthesis of the alcohol intermediate 13 which incorporates a terminal pyrazinone moiety.
- the amide of a suitably substituted amino acid 11 is formed and reacted with glyoxal to form the pyrazine 12, which then undergoes the Ullmann coupling to form intermediate 13.
- Scheme 39 illustrates synthesis of an instant compound wherein a non-hydrogen R9t> is incorporated in the instant compound.
- a readily available 4-substituted imidazole 14 may be selectively iodinated to provide the 5-iodoimidazole 15. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 16. Intermediate 16 can then undergo the alkylation reactions that were described hereinabove.
- Scheme 40 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the bicyclic moiety via an alkyl amino, sulfonamide or amide linker.
- the amine 18 may then react under conditions well known in the art with various activated bicyclic moieties to provide the instant compounds shown.
- Scheme 43 illustrates incorporation of an acetyl moiety as the (CR ⁇ 2)pX(CR ⁇ 2)p linker of the instant compounds.
- the readily available methylphenone 25 undergoes the Ullmann reaction and the acetyl is brominated to provide intermediate 26.
- Reaction with the imidazolyl reagent 4 provides, after deprotection, the instant compound 27.
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Abstract
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Cited By (5)
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WO2000067737A2 (fr) * | 1999-05-07 | 2000-11-16 | The Brigham And Women's Hospital, Inc. | UTILISATION D'INHIBITEURS DE HMGCoA REDUCTASE POUR LA PREVENTION DE MALADIES DONT LA PATHOGENESE DEPEND D'UNE NEOFORMATION DE VAISSEAUX SANGUINS |
WO2002078706A1 (fr) * | 2001-03-29 | 2002-10-10 | Pfizer Products, Inc. | Inhibiteurs de farnesyl transferase combines a des inhibiteurs de reductase hmg coa dans le traitement du cancer |
US6645982B2 (en) | 2000-12-19 | 2003-11-11 | Pfizer Inc | Crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxybutanedioate salts and method of production |
US6740757B2 (en) | 2001-08-29 | 2004-05-25 | Pfizer Inc | Enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3h-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1h-quinolin-2-one and salts thereof, useful in the treatment of cancer |
US8222293B2 (en) * | 2004-05-24 | 2012-07-17 | Regents of the University of Carolina | Treating learning deficits with inhibitors of Hmg CoA reductase |
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WO1997036587A1 (fr) * | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | Methode de traitement du cancer |
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WO1997036587A1 (fr) * | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | Methode de traitement du cancer |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000067737A2 (fr) * | 1999-05-07 | 2000-11-16 | The Brigham And Women's Hospital, Inc. | UTILISATION D'INHIBITEURS DE HMGCoA REDUCTASE POUR LA PREVENTION DE MALADIES DONT LA PATHOGENESE DEPEND D'UNE NEOFORMATION DE VAISSEAUX SANGUINS |
WO2000067737A3 (fr) * | 1999-05-07 | 2001-11-15 | Brigham & Womens Hospital | UTILISATION D'INHIBITEURS DE HMGCoA REDUCTASE POUR LA PREVENTION DE MALADIES DONT LA PATHOGENESE DEPEND D'UNE NEOFORMATION DE VAISSEAUX SANGUINS |
US6645982B2 (en) | 2000-12-19 | 2003-11-11 | Pfizer Inc | Crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxybutanedioate salts and method of production |
US6734308B2 (en) | 2000-12-19 | 2004-05-11 | Pfizer Inc | Crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3,- dihydroxybutanedioate salts and method of production |
WO2002078706A1 (fr) * | 2001-03-29 | 2002-10-10 | Pfizer Products, Inc. | Inhibiteurs de farnesyl transferase combines a des inhibiteurs de reductase hmg coa dans le traitement du cancer |
US6740757B2 (en) | 2001-08-29 | 2004-05-25 | Pfizer Inc | Enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3h-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1h-quinolin-2-one and salts thereof, useful in the treatment of cancer |
US7176315B2 (en) | 2001-08-29 | 2007-02-13 | Pfizer Inc | Enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one and salts thereof, useful in the treatment of cancer |
US8222293B2 (en) * | 2004-05-24 | 2012-07-17 | Regents of the University of Carolina | Treating learning deficits with inhibitors of Hmg CoA reductase |
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