WO2000025789A1 - Procede pour traiter l'endometriose - Google Patents

Procede pour traiter l'endometriose Download PDF

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Publication number
WO2000025789A1
WO2000025789A1 PCT/US1999/025001 US9925001W WO0025789A1 WO 2000025789 A1 WO2000025789 A1 WO 2000025789A1 US 9925001 W US9925001 W US 9925001W WO 0025789 A1 WO0025789 A1 WO 0025789A1
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oxo
imidazo
carbonitrile
substituted
unsubstituted
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PCT/US1999/025001
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English (en)
Inventor
Allen I. Oliff
Jackson B. Gibbs
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Merck & Co., Inc.
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Priority claimed from GBGB9900160.4A external-priority patent/GB9900160D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU12301/00A priority Critical patent/AU1230100A/en
Publication of WO2000025789A1 publication Critical patent/WO2000025789A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the present invention relates to methods of preventing and treating endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hype lasiar which comprise.administering to a patient in need thereof an inhibitor of a prenyl-protein transferasel
  • Endometriosis is a disease in which patches of endometrial tissue, which normally is found only in the uterine lining (endometrium), grow outside the uterus.
  • the misplaced endometrial tissue commonly adheres to the ovaries and the ligaments that support the uterus. Because the misplaced endometrial tissue responds to the same hormones that the uterus responds to, it may bleed during the menstrual period, often causing cramps, pain, irritation, and the formation of scar tissue.
  • Endometriosis is estimated to occur in about 10 to 15 percent of menstruating women between the ages of 25 to 44. As many as 25 to 50 percent of infertile women may have endometriosis, which can physically interfere with conception.
  • the aims of treatment of a patient with endometriosis include elimination of the misplaced endometriotic tissue, relief of pain and induction of pregnancy.
  • Current treatments include administration of drugs that suppress the activity of the ovaries and slow the growth of endometrial tissue, surgery to remove the misplaced endometriotic tissue, surgical removal of the uterus, fallopian tubes and/or ovaries, or combinations of those treatments.
  • drugs such as combination estrogen-progestin oral contraceptives, progestins, danazol, and luteinizing hormone-releasing hormone agonist analogs (such as Buserilin, a GnRH agonists) is accompanied by multiple unwanted side-effects associated with hormone modulation, including bleeding between periods, predisposition to osteopoerosis and mood swings.
  • drug treatment doesn't cure endometriosis; the disease usually returns after treatment is stopped.
  • Uterine fibroids which appear in the reproductive years and regress after menopause, are the result of cellular proliferation and differentiation in the uterine tissue regulated by the ovarian steroids.
  • Treatment of a patient suffering from uterine fibroids include surgery and administration of luteinizing hormone-releasing hormone agonist analogs.
  • Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a class of post-translational modification (Glomset, J. A., Gelb, M. H., and Famsworth, 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, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC.
  • Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-terminal to the farnesylated Cys. 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).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type-II
  • GGPTase-LI also called Rab GGPTase
  • prenyl-protein transferase may be used to generally refer to these enzymes, particularly to farnesyl-protein transferase (FPTase) and geranylgeranyl-protein transferase type I (GGPTase-I). These enzymes are found in both yeast and mammalian cells (Clarke, 1992; Schafer, W. R. and Rine, J. (1992) Annu. Rev. Genet. 30:209-237).
  • FPP farnesyl diphosphate
  • geranyl-geranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate.
  • FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gin or Ala.
  • CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme.
  • 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 ⁇ ara, 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 Ras protein is part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. (52:851-891 (1993)).
  • Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al, Science 277:810-812).
  • Inhibitors of farnesyl-protein transferase have been described in two general classes.
  • the first class includes analogs of FPP, while the second is related to protein substrates (e.g., Ras) for the enzyme.
  • 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.
  • 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)).
  • prenyl pyrophosphates are intermediates in many biosynthetic processes, direct inhibition of a prenyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • compositions useful in the treatment of abnormalities of the endometrium are provided.
  • a method of preventing and treating endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hyperplasia is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a prenyl-protein transferase inhibitor.
  • the present invention relates to a method of preventing and treating endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hype ⁇ lasia, which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a prenyl-protein transferase inhibitor.
  • prenyl-protein transferase inhibitor and inhibitor of prenyl- protein transferase refer 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.
  • Prenyl-protein transferases include farnesyl-protein transferase and geranylgeranyl-protein transferase.
  • farnesyl-protein transferase inhibitor and inhibitor of farnesyl-protein transferase likewise refer 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 present invention is not limited in any way by the specific prenyl- protein transferase inhibitor. Either a protein substrate-competitive inhibitor and/or a prenyl pyrophosphate-competitive inhibitor now known or subsequently discovered or developed may be utilized. Prenyl-protein transferase inhibitors useful in the instant invention are described hereinbelow.
  • the term selective as used herein refers to the inhibitory activity of the particular compound against prenyl-protein transferase activity.
  • 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, respectively.
  • the selectivity is at least 100 times or more.
  • the inhibitor of a prenyl-protein transferase is a selective inhibitor of farnesyl-protein transferase and is characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) of less than about 500 nM against transfer of a farnesyl residue to a protein or peptide substrate comprising a CAAXF motif by farnesyl-protein transferase.
  • the selective inhibitor of farnesyl-protein transferase is characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) of less than about 100 nM against transfer of a farnesyl residue to a protein or peptide substrate comprising a CAAXF motif by farnesyl-protein transferase.
  • CAAXF is used to designate a protein or peptide substrate that inco ⁇ orates four amino acid C-terminus motif that is famesylated by farnesyl-protein transferase.
  • CAAXF motifs include (the corresponding human protein is in parentheses): CVLS (H-ras) (SEQ.LD.: 11), CVLM (K4B-Ras) (SEQ.LD.: 1), CVVM (N-Ras) (SEQ.LD.: 3), CKVL (RhoB) (SEQ.LD.: 9), CLLM (PFX) (SEQ.LD.: 10) and CNIQ (Rap2A) (SEQ.LD.: 13). It is understood that certain of the "CAAXF” containing protein or peptide substrates may also be geranylgeranylated by GGTase-I.
  • a method for measuring the activity of the inhibitors of prenyl-protein transferase utilized in the instant methods against transfer of a farnesyl residue to a protein or peptide substrate comprising a CAAXF motif by farnesyl-protein transferase is described in Example 12. It is also preferred that the selective inhibitor of farnesyl-protein transferase 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 IC50 f° r the inhibition of the famesylation of hDJ protein. When measuring such IC50S the assays described in Examples 17 and 18 may be utilized.
  • the selective inhibitor of farnesyl-protein transferase is further characterized by: c) an IC50 (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 IC50 for inhibition of the famesylation of the protein hDJ in cells.
  • the selective inhibitor of farnesyl-protein transferase is further characterized by: d) an IC50 (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-ras-CVLL (SEQ.LD.NO.: 2) dependent activation of MAP kinases in cells.
  • IC50 a measurement of in vitro inhibitory activity
  • H-ras-CVLL SEQ.LD.NO.: 2
  • the inhibitors of a prenyl-protein transferase utilized in the instant invention are efficacious in vivo as inhibitors of both farnesyl- protein transferase and geranylgeranyl-protein transferase type I (GGTase-I).
  • such a dual inhibitor of farnesyl-protein transferase and geranylgeranyl- protein transferase type I which may be termed a Class II prenyl-protein transferase inhibitor, is characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) of less than about 1 ⁇ M for inhibiting the transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion; and b) an IC50 (a measurement of in vitro inhibitory activity) of less than about 500 nM against transfer of a famesyl residue to a protein or peptide substrate comprising a CAAXF motif by farnesyl-protein transferase.
  • an IC50 a measurement of in vitro inhibitory activity
  • such a Class LI prenyl-protein transferase inhibitor is also characterized by: c) inhibition of the cellular prenylation of greater than (>) about 50% of the newly synthesized K4B-Ras protein after incubation of assay cells with the dual inhibitor of farnesyl-protein transferase and geranylgeranyl-protein transferase type I at a concentration of less than ( ⁇ )10 ⁇ M.
  • such a Class II prenyl-protein transferase inhibitor is also characterized by: c) inhibition of the cellular prenylation of greater than (>) about 50% of the newly synthesized K4B-Ras protein after incubation of assay cells with the dual inhibitor of farnesyl-protein transferase and geranylgeranyl-protein transferase type I at a concentration of less than ( ⁇ )5 ⁇ M.
  • CAAXG will refer to such motifs that may be geranylgeranylated by GGTase-I.
  • CAAXG motifs include (the corresponding human protein is in parentheses): CVIM (K4B-Ras) (SEQ.LD.: 1), CVLL (mutated H-Ras) (SEQ.LD.: 2), CVVM (N-Ras) (SEQ.LD.: 3), CILM (K4A-Ras) (SEQ.LD.: 4), CLLL (Rap-IA) (SEQ.LD.: 5), CQLL (Rap-IB) (SEQ.LD.: 6), CSLM (SEQ.LD.: 7), CALM (SEQ.LD.: 8), CKVL (RhoB) (SEQ.LD.: 9), CLLM (PFX) (SEQ.LD.: 10) and CVIL (Rap2B) (SEQ.LD.: 12).
  • CAAXG motif is CVLM (SEQ.LD.: 1). It is understood that some of the "CAAXG" containing protein or peptide substrates may also be famesylated by farnesyl-protein transferase.
  • the modulating anion may be selected from any type of molecule containing an anion moiety.
  • the modulating anion is selected from a phosphate or sulfate containing anion.
  • modulating anions useful in the instant GGTase-I inhibition assay include adenosine 5'-triphosphate (ATP), 2'-deoxyadenosine 5'-triphosphate (dATP), 2'-deoxycytosine 5'-triphosphate (dCTP), b-glycerol phosphate, pyrophosphate, guanosine 5'-triphosphate (GTP), 2'- deoxyguanosine 5'-triphosphate (dGTP), uridine 5'-triphosphate, dithiophosphate, 3'- deoxythymidine 5'-triphosphate, tripolyphosphate, D-myo-inositol 1,4,5-triphosphate, chloride, guanosine 5'-monophosphate, 2'-deoxygua
  • the modulating anion is selected from adenosine 5'-triphosphate, 2'- deoxyadenosine 5'-triphosphate, 2'-deoxycytosine 5'-triphosphate, b-glycerol phosphate, pyrophosphate, guanosine 5'-triphosphate, 2'-deoxyguanosine 5'- triphosphate, uridine 5'-triphosphate, dithiophosphate, 3'-deoxythymidine 5'- triphosphate, tripolyphosphate, D-myo-inositol 1,4,5-triphosphate and sulfate.
  • the modulating anion is selected from adenosine 5 '-triphosphate, b- glycerol phosphate, pyrophosphate, dithiophosphate and sulfate.
  • Examples of assay cells that may be utilized to determine inhibition of cellular processing of newly synthesized protein that is a substrate of an enzyme that can modify the K4B-Ras protein C-terminus include 3T3, C33a, PSN-1 (a human pancreatic carcinoma cell line) and K-ras-transformed Rat-1 cells.
  • Preferred assay cell line has 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 .
  • a method for measuring the activity of the inhibitors of prenyl-protein transferase, as well as the instant combination compositions, utilized in the instant methods against the cellular processing of newly synthesized protein that is a substrate of an enzyme that can modify the K4B-Ras protein C-terminus after incubation of assay cells with the compound of the invention transferase is described in Example 16 and 17.
  • a Class II prenyl-protein transferase inhibitor may also be characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells of less than 5 ⁇ M.
  • a Class U prenyl-protein transferase inhibitor may also be characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells between 0.1 and 100 times the IC50 for inhibiting the famesylation of the protein hDJ in cells; b) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
  • IC50 a measurement of in vitro inhibitory activity
  • a Class II prenyl-protein transferase inhibitor may also be characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 2 fold lower but less than 20,000 fold lower than the inhibitory activity (IC50) against H-ras-CVLL
  • a Class II prenyl-protein transferase inhibitor may also be characterized by: a) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 10-fold lower but less than 2,500 fold lower than the inhibitory activity (IC50) against H-ras-
  • CVLL (SEQ.LD.NO.: 1) dependent activation of MAP kinases in cells; and b) an IC50 (a measurement of in vitro inhibitory activity) against H-ras-CVLL dependent activation of MAP kinases in cells greater than 5 fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the
  • the preferred therapeutic effect provided by the instant method of treatment is the treatment or prevention of endometriosis, inhibition of the growth of uterine fibroids, reduction or elimination of dysfunctional uterine bleeding and inhibition of endometrial hype ⁇ lasia.
  • a pharmaceutical composition which is useful for the treatments of the instant invention may comprise the inhibitor of prenyl-protein transferase 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, com 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 abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethylcellulose 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 useful in the instant methods of treatment 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.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec C ADD-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. For this pu ⁇ ose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • 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 dmg.
  • 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 which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the dmg.
  • Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • 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.
  • the prenyl-protein transferase inhibitor useful in the instant methods of treatment 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 prenyl-protein transferase inhibitor may be useful in further combination with drugs known to supress the activity of the ovaries and slow the growth of the endometrial tissue.
  • drugs include but are not limited to oral contraceptives, progestins, danazol and GnRH (gonadotropin-releasing hormone) agonists.
  • Administration of the prenyl-protein transferase inhibitor may also be combined with surgical treatment (such as surgical removal of misplaced endometrial tissue) where appropriate.
  • Two or more inhibitors of a prenyl-protein transferase may be administered in combination for the instant methods of treatment.
  • such combination products employ the prenyl-protein transferase inhibitor within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • the prenyl- protein transferase inhibitor may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of an inhibitor of prenyl-protein transferase is administered to a mammal undergoing treatment for endometriosis.
  • Administration occurs in an amount 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 dosage that comprises the instant composition includes from about 10 mg to about 3000mg of an inhibitor of prenyl-protein transferase.
  • the daily dosage comprises from about 10 mg to about lOOOmg of an inhibitor of prenyl-protein transferase.
  • a prenyl-protein transferase inhibitor may also be combined with a compound which inhibits HMG-CoA reductase in the methods of treatment of the instant invention.
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • the terms "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; 4,820,850; 4,916,239), pravastatin (PRAVACHOL®; see US Patent Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 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 co ⁇ esponding 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, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-py ⁇ olidine-l '-yl- methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl)aminomethane.
  • a suitable organic or inorganic base particularly
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsamlate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamao
  • Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodmgs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the dmg form and permit the dmg to afford improved therapeutic efficacy.
  • Inhibitors of HMG-CoA reductase may also be used alone for the treatment and prevention of endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hype ⁇ lasia. Compositions and dosages useful in such monotherapy treatment are described in the patents listed hereinabove.
  • a prenyl-protein transferase inhibitor may be combined with a compound which inhibits a fibroblast growth factor (FGF) receptor function in the methods of treatment of the instant invention.
  • FGF fibroblast growth factor
  • a prenyl-protein transferase inhibitor may be combined with a compound which inhibits a urokinase in the methods of treatment of the instant invention.
  • a prenyl-protein transferase inhibitor may also be combined with a compound which inhibits angiogenisis, and thereby inhibit the growth and invasiveness of endometriotic cells, in the methods of treatment of the instant invention.
  • Such inhibitors of angiogenisis include, but are not limited to angiostatin and endostatin.
  • a prenyl-protein transferase inhibitor may also be combined with a compound which inhibits a matrix metallo-proteinase in the methods of treatment of the instant invention.
  • Compounds which have inhibitory activity for a matrix metallo- proteinase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in PCT Pat. Publ. WO 98/34915 in particular on pp. 24-26.
  • a prenyl-protein transferase inhibitor may also be combined with an anti-estrogen compound, such as toremifene and the like, in the methods of treatment of the instant invention.
  • a prenyl-protein transferase inhibitor may alternatively be combined with a selective estrogen receptor modulator (SERM), devoid of uterotrophic activity, in the instant methods of treatment.
  • SERM selective estrogen receptor modulator
  • a prenyl-protein transferase inhibitor may also be combined with an anti-progestin compound and/or an anti- hormonal compound in the methods of treatment of the instant invention.
  • a prenyl-protein transferase inhibitor may be combined with an antagonist or agonist of gonadotropin-releasing hormone (GnRH) in the instant methods of treatment.
  • GnRH antagonists include, but are not limited to, those compounds described in European Appl. 0 219 292 and De, B. et al., J. Med. Chem., 32:2036-2038 (1989), PCT Publ. WO 95/28405, PCT Publ. WO 95/29900 and European Appl. EP 0 679 642.
  • GnRH antagonists are also described in U.S. Pat. Nos. 5,756,507; 5,780,437 and 5,849,764, as well as U.S. Ser. No. 09/115,497 (filed July 14, 1998) and PCT Appl. US 99/15581 (filed July 9, 1999).
  • GnRH agonists include, but are not limited to, leuprolide and the like.
  • Prenyl-protein transferase inhibitor compounds that are useful in the methods of the instant invention and are identified by the properties described hereinabove include: (a) a compound represented by formula (I-a) through (I-c):
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(O)m-, Rl C(O)NRl0-, CN, NO2, (R 10 )2N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NR 0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(O)m-,
  • Rl0c(O)NRl0- CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RIOOC(O)-, N3, -N(RlO)2, or Rl lOC(O)-NRl0- ;
  • R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 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 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(O) m , -NC(O)-, and -N(CORlO)- ;
  • R4 and R5 are independently selected from H and CH3; and any two of R2, R3, R4 and R5 are optionally attached to the same carbon atom;
  • R6, R7 and R 7a are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
  • R6 and R 7 may be joined in a ring
  • R 7 and R 7 a 1 may be joined in a ring
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(O)m-, Rl0C(O)NRl0-, CN, NO2, Rl 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or
  • R lOC(O)NRl0- and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C alkynyl, perfluoroalkyl, F, Cl, Br,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl 0 ⁇ -, Rl lS(O)m-, Rl0C(O)NRl0-, CN, NO2, (RlO) 2 N-C-(NRlO)-, RlOC(O)-, RlOOC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(O) m -, Rl0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-,
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from Cl -C6 alkyl and aryl;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A is S(O) and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O) m ;
  • W is a heterocycle
  • Ci-4 alkyl unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl,
  • n 0, 1, 2, 3 or 4
  • p 0, 1, 2, 3 or 4
  • Rla Rib, RlO, Rl l, m , R2, R3, R6, R7, p , R7a, u , R8, A , A2, V, W, X, n, p, r, s, t and u are as defined above with respect to formula (I-a);
  • R4 is selected from H and CH3;
  • R2, R3 and R are optionally attached to the same carbon atom;
  • R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl OO-, Rl 1 S(O) m -,
  • Rl0C(O)NRl0- CN, NO2, (RlO) N-C-(NRlO)-, RlOc(O)-, Rl ⁇ QC(O)-, N3, -N(RlO) 2 , or RH OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, R lS(O) m -, Rl0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0- ;
  • G is H2 or O
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1 ) C 1 -4 alkyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle. e) HO, f) -S(O) m R 6 , or g) -C(O)NR6R7,
  • Rla, Rib, RlO, Rl 1, m , R2, R3, R6, R7, p , u , R7a, R8, Al, A2, V, W, X, n, r and t are as defined above with respect to formula (I-a);
  • R4 is selected from H and CH3;
  • R2, R3 and R4 are optionally attached to the same carbon atom;
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • Ci-4 alkyl unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O) m R6, or g) -C(O)NR6R7,
  • Y is 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;
  • Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOo, Rl lS(O) m -, RIOC(O)NRK)-, R1 lC(O)O-, (RlO) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, NO2, RlOC(O)-, N3, -N(RlO) , or Rl lOC(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOo, R
  • C alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, Rl lS(O) m -, Rl°C(O)NRl0-, (RlO) 2 NC(O)-, Rl0 2 N-C(NRlO)-.
  • CN RlOC(O)-, N3, -N(Rl ) 2 , and Rl lOC(O)-NRl0-;
  • R6a, R6b, R6C, Rod and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, Rl lS(O) m -, Rl°C(O)NRl0-, (RlO) 2 NC(O)-, Rl lS(O) 2 NRlO-, (RlO) 2 NS(O)2-, RHC(O)O-, Rl0 2 N-C(NRlO)-, CN, NO2, RlOC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, c) unsubstituted C1-C alkyl, d) substituted
  • R7 is selected from: H; Ci-4 alkyl, C3- cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C alkynyl, perfluoroalkyl, F, Cl, Br, RlOo-, Rl lS(O) m -, RIOC(O)NRK)-, (RlO) 2 NC(O)-, Rl lS(O) 2 NRl°-, (Rl°)2NS(O) 2 -, Rl0 2 N-C(NRlO)-, CN, NO2,
  • R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl 1 S(O) m -,
  • Rl0C(O)NRl0- (RlO) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, NO 2 , RlOC(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRlO-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOo-, Rl lS(O)m-, Rl0C(O)NRl0., (RlO) 2 NC(O)-, Rl0 2 N- C(NRl0)-, CN, Rl C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0- ; RlO is independently selected from hydrogen, -C alkyl, benzyl, 2,2,2- trifluoroethyl and aryl;
  • R 1 is independently selected from C1-C6 alkyl and aryl
  • Rl2 is independently selected from hydrogen, -C6 alkyl, -C6 aralkyl, C1-C6 substituted aralkyl, -C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C ⁇ -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • R! 3 is selected from hydrogen, -C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl;
  • V is selected from: a) hydrogen, b) heterocycle, 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-C20 alkenyl, provided that V is not hydrogen if A is S(O) m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Y is 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;
  • Rla, Rib, RIC an( ⁇ Rid are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R °O-, Rl 1 S(O) m -,
  • R3a anc ⁇ R3b are independently selected from H; unsubstituted or substituted Ci-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: 1) aryl or heterocycle, unsubstituted or substituted with: a) Ci-4 alkyl, c) (CH2)pNR 6 R 7 . d) halogen, e) CN,
  • R2 and R ⁇ a 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(O) m , -NC(O)-, and -N(CORl°)-;
  • R2a and R ⁇ a are optionally attached to the same carbon atom
  • R4 is selected from Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R5, R6 and R7 are independently selected from:
  • Ci-C ⁇ alkyl C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,
  • R 6 and R may be joined in a ring; and independently,
  • R5 and R7 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, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R! 2 O-, RHS(O) m -, R 10 C(O)NRl°-, (Rl°)2NC(O)-, R1°2N-C(NR1°)-, CN, NO2, Rl°C(O)-, Rl°OC(O)-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl °O-,
  • R O is independently selected from hydrogen, C1-C6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • Rl 1 is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle
  • Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
  • Al is selected from a bond, -C(O)-, -C(O)NRl°-, -NR 10 C(O)-, O, -N(R 10 )-, -S(O)2N(RlO)-, -N(RlO)S(O)2-, and S(O) m ;
  • a 2 is selected from a bond, -C(O)-, -C(0)NR1°-, -NR1°C(O)-, O, -N(R1 °)-, -S(O)2N(Rl 0)-, -N(Rl °)S(O)2-, S(O) m and -C(Rl d) 2
  • Gl' G2 and G ⁇ are independently selected from H2 and O;
  • W is heterocycle
  • V is selected from: a) heterocycle, and b) aryl;
  • ⁇ l 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) Ci-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) NR 6 R 7 5 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O) m R 4 , g) -C(O)NR6R7, h) -Si(Ci- 4 alkyl) 3 , or i) Ci-4 perfluoroalkyl;
  • ⁇ 2 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, 2, 3 or 4
  • p 0, 1, 2, 3 or 4
  • q is 1 or 2
  • r is 0 to 5
  • s is independently 0, 1, 2 or 3
  • t is 2 to 6
  • u is 4 or 5;
  • Rla, Rib, R1C ? Rid anc ⁇ Rle are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, cycloalkyl, alkenyl, alkynyl, R ⁇ O-, Rl ⁇ S(O) m -, R!
  • R 4 is selected from C ⁇ _4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or
  • R 6 and R7 are independently selected from: 25 1) hydrogen,
  • R 6 and R7 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, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 2 O-, Rl lS(O) m -, R 10 C(O)NR 10 -, (Rl°) 2 NC(O)-, R 10 2N-C(NRl°)-, CN, NO2, R 10 C(O)-, Rl°OC(O)-, N3, -N(Rl°)2, or RHOC(O)NR 10 -, and c) C 1 -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C
  • RlO is independently selected from hydrogen, Ci-C ⁇ alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • R 1 is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • R 2 is independently selected from hydrogen, -C6 alkyl, C1-C3 perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
  • A is selected from a bond, -C(O)-, -C(O)NRl°-, -NR1°C(0)-, O, -N(R 10 )-, -S(O) 2 N(RlO)-, -N(R 1 () )S(O)2-, and S(O) m ;
  • A is selected from a bond, -C(O)-, -C(0)NR1°-, -NR!OC(O)-, O, -N(R 10 )-, -S(O)2N(RlO)-, -N(Rl n )S(O)2-, S(O) m and -C(Rld) 2 - ;
  • W is heteroaryl
  • V is selected from: a) heteroaryl, and b) aryl;
  • X and Y are independently selected from -C(O)-, -C(O)NRl°-, -NR1 °C(0)-, -NRl°C(O)-O-, -O-C(O)NRl°-, -NRl°C(O)NRl°-, -C(O)NRl°C(O)-, O, -N(R1 °)-, -S(O) 2 N(RlO)-, -N(RlO)S(O)2- and S(O) m ;
  • 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:
  • C3-C6 cycloalkyl is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or more of:
  • n 0, 1, 2, 3 or 4
  • p O, 1, 2, 3 or 4
  • q is 1 or 2
  • r is 0 to 5
  • s is independently 0, 1, 2 or 3
  • t is 1, 2, 3 or 4
  • v is 2 to 6;
  • Rla, R b, RIC a ⁇ Rle are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R °O-, Rl 1 S(O) m -,
  • Rl°C(O)NR 10 - (R 10 )2N-C(O)-, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, Rl°OC(O)-, N3, -N(Rl°)2, or Rl l ⁇ C(O)NR 10 -, c) unsubstituted or substituted Ci-C ⁇ alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl ⁇ O-,
  • Rl lS(O)m- R 10 C(O)NRl0-, (R 10 )2N-C(O)-, CN, (RlO) 2 N- C(NRl°K R 10 C(O)-, RIOOC(O)-, N3, -N(Rl°)2, and Rl l ⁇ C(O)- NR10-; or two R as, two R ⁇ s, two Rl c s or two R e s, on the same carbon atom may be combined to form -(CH2)vS
  • R 4 is selected from Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R 6 and R7 are independently selected from: 1) hydrogen, 2) Rl °C(O)-, or R 1 °OC(O)-, and
  • Ci-C ⁇ alkyl C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C6-C10 multicychc alkyl ring, unsubstituted or substituted with one or more substituents selected from: a) RlOO-, b) aryl or heterocycle, c) halogen, d) R 10 C(O)NR 10 -, p10 e)
  • R 6 and R7 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, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 2 O-, RHS(O) m -, R 10 C(O)NRl°-, (R 10 )2NC(O)-, Rl°2N-C(NRl°)-, CN, NO2, Rl°C(O)-, R!
  • °OC(O)- c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(O)m-, R 10 C(O)NH-, (Rl°)2NC(O)-, R1 °2N-C(NR1°)-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R °O-,
  • Rl lS(O)m- R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRl°)-, CN, NO2, R 10 C(O)-, R 10 OC(O)-, N3, -N(Rl°)2, or Rl iOC ⁇ NRl 0 -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R OO-, RHS(O) m -, R 10 C(O)NRl0-, (Rl°)2NC(O)-, R 10 2N- C(NR!0)-, CN, R 10 C(O)-, Rl°OC(O)-, N3, -N(R10) 2 , or
  • RlO is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • R is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
  • Al is selected from a bond, -C(O)-, -C(O)NRl°-, -NR1 °C(0)-, O, -N(R1°)-, -S(O)2N(RlO)-, -N(RlO)S(O)2-, and S(O) m ;
  • a 2 is selected from a bond, -C(O)-, -C(O)NRl°-, -NR1 °C(0)-, O, -N(R1°)-, -S(O) 2 N(RlO)-, -N(RlO)S(O)2-, S(O) m and -C(Rld) 2 -;
  • W is heteroaryl
  • V is selected from: a) heteroaryl, and b) aryl;
  • X is independently selected from -C(O)-, -C(0)NR1°-, -NR 10 C(O)-, -NR 10 C(O)-O-, -O-C(O)NR 10 -, - NR1°C(0)NR1°-, -C(0)NR1°C(0)-, O, -N(R i 0 )-, -S(O)2N(R 10 )-, -N(Rl °)S(O)2- and S(O) m ;
  • 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:
  • Z is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or more of:
  • n 0, 1, 2, 3 or 4
  • p 0, 1, 2, 3 or 4
  • q is 1 or 2
  • r is 0 to 5
  • s is independently 0, 1, 2 or 3
  • t is 1, 2, 3 or 4
  • v is 2 to 6;
  • the prenyl-protein transferase inhibitor is a compound represented by formula (IV):
  • Rla, Rib, Rle and Rid are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, RiiS(O) m -, Rl0C(O)NRl0-, (RlO) 2 N-C(O)-, CN, NO2,
  • R2a, R2b, R3a and R3b are independently selected from: H; unsubstituted or substituted _ 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 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(O)m, -NC(O)-, and -N(CORlO)-;
  • R2 and R3 are optionally attached to the same carbon atom
  • R4 is selected from: Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ⁇
  • R5, R 6 and R7 are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R 6 and R7 may be joined in a ring; and independently, R5 and R7 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, C2-C6 alkenyl, C2-C alkynyl, perfluoroalkyl, F, Cl, Br, Rl0 ⁇ , Rl lS(O) m -, Rl0C(O)NRl0-, (RlO) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, NO2, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 al
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl OO-,
  • Rl lS(O)m- R 10 C(O)NRl0-, (RlO)2NC(O)-, Rl0 2 N-C(NRlO)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOo-, Rl lS(O)m-, R 10 C(O)NRl0-, (RlO) 2 NC(O)-, Rl 2 N- C(NRlO)-, CN, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0- ;
  • R O is independently selected from hydrogen, C1-C6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • Rl 1 is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
  • A is selected from: a bond, -C(O)-, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(O) 2 N(R10)-, -N(RlO)S(O) 2 -, and S(O) m ;
  • A2 is selected from: a bond, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(R10)-, -S(O) N(RlO)-, -N(RlO)S(O)2-, S(O) m and -C(Rld) 2 -;
  • Gl, G2 and G3 are independently selected from: H2 and O;
  • W is heterocycle
  • V is selected from: 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:
  • Ci-4 alkyl unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O) m R 4 or g) -C(O)NR 6 R7,
  • 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: 1) C 1-4 alkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR 6 R 7 , c ) C3- cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O) m R 4 , or g) -C(O)NR 6 R 7 ,
  • n 0, 1, 2, 3 or 4
  • p is O, 1, 2, 3 or 4
  • q is 1 or 2
  • r is O to 5
  • s is independently 0, 1, 2 or 3
  • u is 4 or 5;
  • Examples of compounds which inhibit prenyl protein transferase include the following: 2(S)-Butyl- 1 -(2,3-diaminoprop- 1 -yl)- 1 -( 1 -naphthoyl)piperazine;
  • prenyl-protein transferase inhibitor examples include:
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
  • substituted alkyl 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 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present.
  • alkenyl groups examples include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1 -propenyl, 2- butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, 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 phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted as defined below.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
  • 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 tetrahydroimidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic or stable 11-15 membered tri cyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazoly
  • heterocycle is selected from imidazolyl, 2- oxopyrrolidinyl, piperidyl, pyridyl and pyrrolidinyl.
  • substituted aryl substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Ci-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)O-, -OH, (Ci-C ⁇ alkyl)S(O) m -, ( -C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(
  • the compounds used in the present method may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • named amino acids are understood to have the natural "L" stereoconfiguration.
  • fused ring moieties may be further substituted by the remaining R 6a , R 6 b, R 6c , R 6 d 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 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:
  • fused ring moieties may be further substituted by the remaining R 6a , R 6 b, R 6( R d and/or R 6e as defined hereinabove.
  • 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:
  • cyclic moieties are formed.
  • cyclic moieties include, but are not limited to:
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • any substituent or variable e.g., RlO, Z, n, etc.
  • -N(RlO)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • DMAP 4-Dimethylaminopyridine
  • DME 1,2-Dimethoxyethane
  • 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 dmg.
  • pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • Non-toxic salts include conventional non-toxic salts or quartemary 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 present 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 prenyl protein transferase inhibitors of formula (I-a) through (I-c) can be synthesized in accordance with Schemes 1-22, 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 R2, R3, R4, and R5' however their point of attachment to the ring is illustrative only and is not meant to be limiting.
  • These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.
  • Boc-protected amino acids I available commercially or by procedures known to those skilled in the art, can be coupled to N- benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide.
  • dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethylformamide.
  • the product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine Ifl.
  • acid for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine Ifl.
  • Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IN, which is protected as the Boc derivative V.
  • the ⁇ -benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Pan apparatus for 24-48 h.
  • the product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII; a final acid deprotection as previously described gives the intermediate VIJI (Scheme 2).
  • the intermediate VHI can be reductively alkylated with a variety of aldehydes, such as DC
  • 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 3).
  • 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 X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride.
  • the final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
  • the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as 1 -trityl-4-imidazolyl- carboxaldehyde or 1 -trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 4).
  • the trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVffl.
  • the intermediate NIH can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII.
  • Hydrolysis and reaction with piperazine Vfll in the presence of condensing reagents such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
  • the piperazine VHI is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7).
  • 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 XXIX.
  • the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.
  • the Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8).
  • the aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXHI.
  • piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX.
  • R' is an aryl group
  • XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL.
  • the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
  • ⁇ -Aryl piperazines can be prepared as described in Scheme 11.
  • An aryl amine XLV is reacted with bis -chloroethyl amine hydrochloride (XL VI) in refluxing n -butanol to furnish compounds XLVII.
  • the resulting piperazines XLVII can then be carried on to final products as described in Schemes 3-9.
  • Piperazin-5-ones can be prepared as shown in Scheme 12. Reductive amination of Boc-protected amino aldehydes XLIX (prepared from I as described previously) gives rise to compound L.
  • the isomeric piperazin-3-ones can be prepared as described in Scheme 13.
  • the imine formed from arylcarboxamides LU and 2-aminoglycinal diethyl acetal (LIU) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV.
  • Amino acids I can be coupled to amines LIN under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI.
  • Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9.
  • Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R ⁇ and R ⁇ are combined to form -(CH2) ⁇ -
  • 1-aminocyclohexane-l -carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2.
  • the piperazine intermediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9.
  • the aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16.
  • the product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base- induced cyclization to LXXHI.
  • Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI.
  • Scheme 17 illustrates the use of an optionally substituted homoserine lactone LXXIX to prepare a Boc-protected piperazinone LXXXII.
  • Intermediate LXXXII may be deprotected and reductively alkylated or acylated as illustrated in the previous Schemes.
  • the hydroxyl moiety of intermediate LXXXII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate LXXXIIL
  • Intermediate LXXXII may also be oxidized to provide the carboxylic acid on intermediate LXXJV, which can be utilized form an ester or amide moiety.
  • Amino acids of the general formula LXXXVI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 18 starting with the readily prepared imine LXXXV.

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Abstract

L'invention concerne un procédé permettant de prévenir et de traiter l'endométriose, les fibromes utérins, la ménométrorragie, et l'hyperplasie endométriale, ce procédé consistant à administrer une quantité efficace d'un inhibiteur de prényl-protéine transférase à un patient mammifère nécessitant un tel traitement.
PCT/US1999/025001 1998-10-29 1999-10-25 Procede pour traiter l'endometriose WO2000025789A1 (fr)

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WO2002064142A1 (fr) * 2001-02-15 2002-08-22 Janssen Pharmaceutica N.V. Combinaisons d'inhibiteurs de la farnesyle proteine transferase avec agents anti-oestrogene
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