WO2005058298A2 - Analogues de fk228 et methodes de production et d'utilisation desdits analogues - Google Patents

Analogues de fk228 et methodes de production et d'utilisation desdits analogues Download PDF

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WO2005058298A2
WO2005058298A2 PCT/US2004/041678 US2004041678W WO2005058298A2 WO 2005058298 A2 WO2005058298 A2 WO 2005058298A2 US 2004041678 W US2004041678 W US 2004041678W WO 2005058298 A2 WO2005058298 A2 WO 2005058298A2
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histone deacetylase
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compound
inhibiting
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Scott R. Rajski
David A. Wassarman
Jose A. Restituyo
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Wisconsin Alumni Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention relates to the inhibition of histone deacetylase. More particularly, the invention is directed to analogs of the anti-cancer drug FK228 and methods of making and using the same.
  • FK228 (1 ), formally known as FR901 228, is a histone deacetylase (HDAC) inhibitor possessing anti-tumor activity but very little toxicity in normal cells (Richon et al., 1 998, Proc. Natl. Acad. Sci. USA, 95: 3003-3007).
  • HDAC histone deacetylase
  • FK228 is in clinical studies for chromic lymphocytic leukemia, small lymphocytic lymphoma, acute myeloid leukemia, cutaneous T-cell lymphoma, and refractory small cell lung cancer.
  • chemical syntheses of FK228 have proven difficult and yields of the natural product from microbial cultures are disappointingly inadequate.
  • compositions for inhibiting a histone deacetylase based upon novel structurally simple analogs of FK228 comprise a novel analog represented by the general formula:
  • the compound includes an Ri group that is a tert-butyldiphenylsilyl (TBSPS-0-) group or
  • Ri is a cap structure selected from the group consisting of:
  • compositions according the invention include a compound having the formula:
  • composition according to the invention may have the formula:
  • compositions for inhibiting a histone deacetylase comprising a cyclic FK228 analog represented by the general formula:
  • n is an integer from 1 to 7; and wherein Ri is -OH, RCONH2 or a cap structure wherein R is selected from the group consisting of unsubstituted and substituted alkyls, alkenyls, alkynyls, cycloalkyls, aryls, heterocyclyls and the cap structure is selected from the group consisting of unsubstituted and substituted alkyls, alkenyls, alkynyls, cycloalkyls, aryls, heterocyclyls, phthalimides, naphthalimides and polycyclic phenols.
  • n 3
  • Certain cyclic disulfide compounds may further include Ri as a cap structure selected from the group consisting of:
  • the cyclized disulphide for inhibiting a histone deacetylase is synthesized by the following the method.
  • the method includes the steps of chemically converting (a) a bromoacid to a corresponding dit ⁇ tylated ester (b) the dit ⁇ tylated ester to a corresponding macrocycle (c) the macrocycle to a corresponding cyclized disulphide compound via reduction for inhibiting a histone deacetylase.
  • Methods provided by the present invention for synthesizing cyclic disulfides may further include the additional step of coupling the cyclized disulfide compound to a targeting agent
  • Useful targeting agents include monoclonal antibodies or other agents known to accumulate in tumors, such as N-benzylpolyamines, porphyrms and related small molecules, as well as the capping structures disclosed herein.
  • Another embodiment of the present invention provides a compound produced by the method of any of claims 1 0 or 1 4, or paragraphs 1 9 and 20.
  • compositions for inhibiting a histone deacetylase include compounds and compositions as described and claimed herein.
  • Another embodiment of the present embodiment includes a method of eliciting a chemopreventive effect for a disease in a patient comprising the step of administering a pharmaceutically effective amount of a composition according to the invention to a patient are further encompassed by the invention.
  • FIG. I is a schematic representation of a mechanism depicting how, under normoxic conditions, HIF-1 a is degraded by the ubiquitin-proteosome system in a process that relies upon the von Hippel Lindau (VHL) tumor suppressor protein.
  • VHL von Hippel Lindau
  • FIG. 2 is a schematic representation depicting the use of e-caprolactone to genrate free thiol 29.
  • the inventors conducted the reaction sequence indicated in the scheme, and subsequently assayed for HDAC inhibition of simple C5 linked thiols, which are precursors to cyclic disulfides, to demonstrate that alkylthiols are effective HDAC inhibitors.
  • FIG. 3 depicts the bioactivity of disulfide precursors (A) 27, 28, and 33 and (B) 34, 31 and 32 using Drosophila Sl cells and immunoprecipitation studies.
  • FIG. 4 is a schematic representation depicting a general structure of a cyclic FK228 analog according to the invention.
  • FIG. 5 illustrates a partial library of cyclic disulfide FK228 analogs according to the invention.
  • FIG. 6(a) depicts the conversion of a lactone to a cyclic disulfide according to the present invention
  • (b) depicts a preferred method for construction of cyclic disulphides according to the present invention.
  • FIG. 7 Western blot analysis of histones isolated from Drosophila S2 cells treated with cyclic disulfides 125b-d
  • a "therapeutically effective amount” is the amount effective to inhibit the growth of the tumor(s) in vivo.
  • An effective amount of a histone deacetylase inhibitor or an effective amount of a FK228 analog used as a histone deacetylase inhibitor is preferably the amount of either of these substances that is effective in inhibiting the growth of tumor(s) when administered to a patient suffering from a diseased state.
  • alkyl refers to the group of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C ⁇ -C 3 o for straight chain, C 3 -C 30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 4-1 0 carbon atoms in their ring structure, and more preferable have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • alkyl (or “lower alkyl) as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, carbonyl (such as a carboxylate, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl, arylcarbonyl, aldehyde, and the like), thiocarbonyl (such as a thioacid, alkoxycarbonyl, and the like), an alkoxyl, unsubstituted amino, mono- or disubstituted amino, amido, amidine, imine, nitro, azido, sulfhydryl, alkylthio, cyano, trifluoromethyl, sulfonato, sulfamoyl, sulfonamido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
  • carbonyl such as a carboxylate, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl, arylcarbonyl, aldeh
  • moieties substituted on the hydrocarbon chain can themselves by substituted, as described above, if appropriate.
  • exemplary substituted alkyls are described below.
  • Cycloalkyls can be further substituted with, e.g., alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, - CF 3 , -CN, and the like.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • enyne refers to an unsaturated aliphatic moiety having at least one double bond and one triple bond.
  • alkylidene alkenylidene
  • alkynylidene are art- recognized and refer to moieties corresponding to alkyl, alkenyl, and alkynyl moieties as defined above, but having two valences available for bonding.
  • aryl as used herein includes 5-, 6- and 7-membered ring aromatic groups that may include from zero to four heteroatoms, for example, phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyraszolyl, pyridyl, pyrazinyl, pyrimidyl, and the like. Those aryl s having heteroatoms in the ring structure may also be referred to as “aryl heterocycles" or "heteroaromatics".
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, carboyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, carboyl, carboxyl, silyl
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • heterocyclyl refers to non-aromatic 4- to 1 0-membered ring structures, more preferable 4- to 7-membered rings, which ring structures include one to four heteroatoms (e.g., O, N, S, P and the like).
  • Heterocyclyl groups include, for example, pyrrolidine, oxolane, thiolane, imidazole, oxazone, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
  • the heterocyclic ring can be substituted at one or more positions with such substitutents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, alkoxycarbonyl, aryloxycarbonyl, carboxyl, silyl, ether,, alkylthio, alkylsulfonyl, arylsulfonyl, ketone (e.g., -C(0)-alkyl or -C(O)- aryl), aldehyde, heterocyclyl, an aryl or heteroaryl moiety, -CF 3 , -CN, or the like.
  • substitutents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino
  • FK228 analogs which have not been made in vitro prior to the teachings of the present inventors in the references cited herein, or to FK228 analogs which have never been produced synthetically prior to the teachings of the present inventors in the references cited herein, or to FK228 analogs that are completely novel and have never been produced via natural or chemical syntheses.
  • HDAC1 histone deacetylases 1
  • Angiogenesis The growth of new blood vessels into a cancer (angiogenesis) is required for continued growth of the tumor mass beyond 1 -2 mm 3 .
  • Tumor hypoxia is a major inducer of vascular endothelial growth factor (VEGF) gene expression (Kim et al., 2001 , Nature Medicine 7: 437-443).
  • VEGF vascular endothelial growth factor
  • VEGF expression is under the control of the hypoxia-inducible factor (HIF-1 ), a heterodimeric transcription factor recognized as the key regulator of the hypoxia response in a variety of cell types (Kim et al., 2001 , Nat. Med. 7: 437-443; Semenza, 2000, Cancer and Metastatis Rev. 1 9: 56-65; Semenza, 2001 , Curr. Op. Cell Biol. 1 3: 1 67-1 71 ; Ratcliffe et al., 2000, Nat. Med. 6: 1 31 5-1 31 6). Composed of HIF- 1 « and HIF-1 ⁇ , HIF-1 activates the transcription of genes encoding angiogenic growth factors and vasomotor regulators.
  • HIF-1 hypoxia-inducible factor
  • HIF-1 also regulates the expression of molecules involved in matrix modeling, iron transport/regulation and apoptosis/cell) proliferation (Semenza, 2000, Cancer and Metastatis Rev. 1 9: 56-65; Semenza, 2001 , Curr. Op. Cell Biol. 1 3: 1 67-1 71 ; Ratcliffe et al., 2000, Nat. Med. 6: 1 31 5-1 31 6).
  • HIF-1 w is constitutively expressed, whereas HIF-1 ⁇ is induced by exposure of cells to hypoxia or growth factors.
  • HIF expression levels are characteristically increased in many cancerous tumor types as are a number of reductases (Saramaki et al., 2001 , Cancer Gen. and Cytogen. 1 28: 31 -34; Huss et al., 2001 , Cancer Res. 61 : 2736-2743; Cvetkovic et al., 2001 , Urology 57: 821 -825).
  • HIF-1 ⁇ is degraded by the ubiquitin-proteosome system. This process relies upon the von Hippel Lindau (VHL) tumor suppressor protein; interaction with HIF-1 ⁇ affords the recognition component of an E3 ubiquitin ligase complex (Kim et al., 2001 , Nat. Med. 7: 437-443). Hypoxia-associated reduction of VHL levels leads to HIF-1 ex accumulation and subsequent overexpression of proangiogenic (metastasis-associated) agents. Hypoxia and HIF-1 ex overexpression are hallmarks of many tumor types, particularly prostate carcinomas (Saramaki et al., 2001 , Cancer Gen. and Cytogen. 1 28: 31 -34; Cvetkovic et al., 2001 , Urology 57: 821 -825).
  • VHL von Hippel Lindau
  • HDAC1 histone deacetylase 1
  • Kim et al., 2001 , Nat. Med. 7: 437-443; Williams, 2001 , Expert Opin. Invest. Drugs 1 0: 1 571 -1 573; Furumai et al., 2002, Cancer Res. 62: 491 6-4921 Hypoxia-dependent upregulation of HDAC1 negatively regulates VHL levels which in turn enhances HIF-1 ⁇ .
  • TSA and FK228 do not exclusively target HDAC1 . That HDAC1 inhibition by TSA is not specific to hypoxic cells is consistent with the notion that 2, like most effective HDAC inhibitors (IC50 ⁇ 50nM), does not require an activating event en route to expression of bioactivity (Breslow et al., 2000, Helv. Chim. Acta 83: 1 685-1 692; Marks et al., 2001 , Curr. Op. Oncol. 1 3: 477-483; Hassig and Schreiber, 1 997, Curr. Op. Chem. Biol. 1 , 300-308-; Hung et al., 1 996, Chem. Biol.
  • FK228 (1 ) is the one exception to this rule; intracellular disulfide ⁇ dithiol conversion is required for effective HDAC inhibition and is at the heart of FK228s very promising future (Furumai et al., 2002). FK228 does in fact require intracellular disulfide cleavage, but this provides the lone example of a bioactivated HDAC inhibitor.
  • Trx is found in high levels in many human cancers and increases both aerobic and hypoxia-induced HIF-1 ex concentrations promoting the notion that Trx-activated agents are likely to display beneficial tumor cell selectivity (Shao et al., 2001 ; Becker et al., 2000; Arner et al., 2000).
  • the likelihood that FK228 undergoes Trx-mediated activation has been proposed as a critical element behind its potent antitumor activity (Furumai et al., 2002; Kwon et al., 2002).
  • GSH has also been implicated in FK228 activation and presents another possible manifold by which tumor cell selectivity arises. This is particularly significant since enhanced GSH levels represent one manifold by which drug resistance arises in tumor cells.
  • FK228 is currently in Phase I clinical trials for thyroid and other advanced malignancies, combination therapy for lung cancer, and also for leukemias.
  • the agent is in Phase II clinical trials for T cell lymphomas and other phase II projections involving Non-Hodgkins lymphoma and acute myelogenous leukemia, and pancreatic cancer. Alarmingly, many of these trials have been hindered due to a shortage of the natural product (Li et al., 1 996, J. Am. Chem. Soc. 1 1 8: 7237-7238).
  • HDACs mediate gene expression through deacetylation of N-acetyl lysine residues contained within histone proteins and other transcriptional regulators (Prives and Manley, 2001 , Cell 1 07: 81 5-81 8). How this covalent modification to histone proteins elicits changes at the transcriptional level is not mechanistically well understood; a lack of HDAC- specific inhibitors is largely to blame.
  • Highly refined tools for the global analysis of HDAC function are now available yet tools with which to perturb HDAC function are still in their infancy. Methods for the temporal control of gene expression would allow the differentiation between direct, early effects and indirect, late effects and are most certainly needed to formulate coherent drug design and discovery processes that capitalize on HDACs.
  • HDAC activity/function is implicated in a wide array of malignant diseases (Kwon et al., 2002, Int. J. Cancer 97: 290-296; Dieter, 2000, Mol. Med. 6: 623-644; Kelly et al., 2002, Expert Op. Invest. Drugs 1 1 : 1 695-1 71 3; Vigushin et al., 2002, 1 3: 1 -1 3; Minucci et al., 2001 , Oncogene 20: 31 1 0-31 1 5).
  • HDACs have also been found to be overexpressed under specific environmental conditions such as hypoxia, hypoglycemia and serum deprivation and it is now also apparent that HDAC inhibitors may have use as agents to combat infectious disease (Smith et al., 2002, Antimicrobial Agents & Chemotherapy 46: 3532-3539; Klar et al., 2001 , Genetics 1 58: 91 9-924; Andrews et al., 2000, Int. J. Parasit. 30: 761 -768).
  • HDAC recognition or affinity "cap” is attached to an enzyme active site binding/inactivating group (3, boxed region), via a linker devoid of elaborate functionality (Breslow et al., 2000, Helv. Chim. Acta 83: 1 685-1 692; Marks et al., 2001 , Curr. Op. Oncol. 1 3: 477-483).
  • An HDAC recognition or affinity "cap” is attached to an enzyme active site binding/inactivating group (3, boxed region), via a linker devoid of elaborate functionality (Breslow et al., 2000, Helv. Chim. Acta 83: 1 685-1 692; Marks et al., 2001 , Curr. Op. Oncol.
  • N-alkylated indole analogs of apicidin show a greater than 20-fold preference for targeting malarial HDACs over human HDAC1 (Colletti et al., 2000, Tet. Lett. 41 : 7825-7829).
  • Efforts to make and identify HDAC inhibitors with useful specificity or selectivity continue to focus on new types of structures yet the lesson taught by FK228 that linker restriction via cyclization can lead to triggerable inhibitors appears to have gone either unnoticed or unheeded.
  • compositions for inhibiting a histone deacetylase based upon novel structurally simple analogs of FK228 comprise a novel analog represented by the general formula:
  • the compound includes an Ri group that is a tert-butyldiphenylsilyl (TBSPS-0-) group or
  • Ri is a cap structure selected from the group consisting of:
  • compositions according the invention include a compound having the formula:
  • composition according to the invention may have the formula:
  • compositions for inhibiting a histone deacetylase comprising a cyclic FK228 analog represented by the general formula:
  • n is an integer from 1 to 7; and wherein Ri is -OH, RCONH 2 or a cap structure wherein R is selected from the group consistin ⁇ of unsubstituted and substituted alkyls, alkenyls, alkynvls, cycloalkyls, aryls, heterocyclyls and the cap structure is selected from the group consisting of unsubstituted and substituted alkyls, alkenyls, alkynyls, cycloalkyls, aryls, heterocyclyls, phthalimides, naphthalimides and polycyclic phenols.
  • n 3.
  • Certain cyclic disulfide compounds may further include Ri as a cap structure selected from the group consisting of:
  • the cyclized disulphide for inhibiting a histone deacetylase is synthesized by the following the method.
  • the method includes the steps of chemically converting (a) a bromoacid to a corresponding ditritylated ester (b) the ditritylated ester to a corresponding macrocycle (c) the macrocycle to a corresponding cyclized disulphide compound via reduction for inhibiting a histone deacetylase.
  • Methods provided by the present invention for synthesizing cyclic disulfides may further include the additional step of coupling the cyclized disulfide compound to a targeting agent.
  • Useful targeting agents include monoclonal antibodies or other agents known to accumulate in tumors, such as N-benzylpolyamines, porphyrins and related small molecules, as well as the capping structures disclosed herein.
  • the cyclized disulphide compound may also have a capping group as discussed above.
  • compositions for inhibiting a histone deacetylase are provided which include compounds and compositions as described and claimed herein.
  • Another embodiment of the present embodiment includes a method of eliciting a chemopreventive effect for a disease in a patient comprising the step of administering a pharmaceutically effective amount of a composition according to the invention to a patient are further encompassed by the invention.
  • the invention is preferably directed to synthesis and evaluation of redox activated histone deacetylase (HDAC) inhibitors.
  • HDAC histone deacetylase
  • trapoxin B (3) and depsipeptide FK228 (1 ) display impressive anticancer activities by virtue of their capacity for HDAC inhibition.
  • FK228 appears to have any cell selectivity. Intracellular cleavage of the FK228 disulfide allows for linker linearization and subsequent active site metal binding by the thiol capped butene moiety.
  • GSH glutathione
  • the present invention further includes pharmaceutical compositions for the treatment or prophylaxis of tumor, inflammatory disorders, diabetes, diabetic complication, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia, organ transplant rejection, and autoimmune disease.
  • Pharmaceutical composition, according to the invention comprise an FK228 analog or salts thereof as an active ingredient.
  • this invention teaches HDAC-inhibiting cyclized prodrugs having functional analogy to FK228.
  • Linker restriction of structurally diverse HDAC inhibitors is used to obtain cell selectivity on the basis of altered redox enzyme expression levels.
  • the invention encompasses the generation of HDAC inhibitors capable of expressing activity only after an S-S bond scission events. Conformational restriction of the linker portion of HDAC inhibitors analogous to FK228 will inhibit the expression of significant biological activity at undesired cellular locations. The inability of the linkage between drug pharmacophore and cap unit to assume a linear conformation will prohibit delivery of the pharmacophore to the HDAC active site.
  • Trx may directly inactivate electrophilic drugs in a suicide inhibition motif (Herzig et al., 1 999, Biochem. Pharm. 58: 21 7-225; Brandes et al., 1 993, J. Biol. Chem. 268: 1 841 1 -1 841 4). Both Trx and glutathione overexpression are signatures of drug resistant cells (Husbeck and Powis, 2002, Carcinogenesis 23: 1 625-1 630; Herzig et al., 1 999, Biochem. Pharm.
  • Trx inhibition has been intensively examined as a means by which to remediate tumor cell resistance to classical chemotherapeutic agents (Moos et al., 2003, J. Biol. Chem. 278: 745-750; Naito et al., 1 999, Int. J. Urology 6: 427-439). These considerations promote the notion that Trx takes part in the mechanism of activation for FK228 and that novel agents based on the FK228 structure will capitalize on a similar mode of activation.
  • FIG. 2 The inventors have initially conducted the synthesis shown by FIG. 2, and have subsequently assayed for HDAC inhibition of simple C5 linked thiols, which are precursors to cyclic disulfide analogs of FK228 as represented by 21 .
  • one preferred pathway to compounds according to the invention is via hydrolysis of C-caprolactone 23 using Nicolaou conditions followed by immediate alcohol silylation affords acid 24 which undergoes facile coupling to benzyl thioether 25 (Nicolaou et al., 1 993, J. Am. Chem. Soc. 1 1 2: 3040- 3055).
  • the resulting amide 26 is readily converted to the hydroxymethyl analog 27, followed by tert-butyldiphenylsilyl (TBDPS) protection of the hydroxymethyl moiety and subsequent selective desilylation of the €-oxygen (Zhu et al., 2000, J. Chem. Soc. Perkin I 1 5 2305-2306).
  • TDPS tert-butyldiphenylsilyl
  • the resulting alcohol 27 is obtained in 80% yield from fully protected 26.
  • Alcohol 27 is readily converted to the thioacetyl analog using methodology originally disclosed by Volante (Volante, 1 981 , Tet. Lett. 22: 31 1 9-31 22). Deacetylation of 28 is readily effected with sodium methoxide to afford free thiol 29.
  • the synthetic intermediates 27, 28, and 29, also as shown in FIGs. 1 and 2 represent a number of related compounds bearing the C5 linker.
  • these compounds 27, 28, 29 and 33 have either D/L stereo configuration.
  • these compounds 27, 28, 29 and 33 have L stereo configuration.
  • C5 linker- based molecules constructed include 31 -34; all but 33 bear the same capping 1 ,8- naphthalimide structure as Scriptaid, a known HDAC inhibitor displaying roughly 1 /3 the potency of TSA (Su et al., 2000, Cancer Res. 60: 31 37-31 42).
  • Naphthalimide 31 is derived from UBH4 reduction of 26 followed by Mitsunobu coupling to 1 ,8-naphthalimide and subsequent generation of the acetylthiol in a fashion paralleling the conversion of 27 to 28.
  • Alcohols 27, 33 and 34 serve as control compounds which allow a careful dissection of the roles played by the thiol, thioester, and simplistic cap groups of 28 - 32 as well as other agents based on the C5 linked thiols and thioesters.
  • the results of biological studies provide direction in terms of linker lengths compatible with thiol-induced HDAC inhibition.
  • Lysates are then be subjected to differing concentrations of HDAC inhibitors and/or reductants (Barlow et al., 2001 , Exp. Cell Res. 265: 90-1 03). The need to supplement these lysates with acetylated histones is then determined. Although the preferred method of acetyl Lys detection relies upon established Western blotting methods (Ballestar et al., 2001 , Eur. J. Biochem.
  • Pane/ A depicts Western blot analysis of histones isolated from Drosophila S2 cells treated with first generation cyclic disulfide precursors 27, 28 and 33. H2B detection was used to ensure equivalent protein loading to each well. Dark bottom bands most prominent in lanes 2,3, 5 and 6 indicate the enhanced abundance of tetra-AcLys H4, consistent with HDAC inhibition. Lanes 1 and 4 correspond to drosophila cells subjected to the "control" compound
  • Panel B depicts Western blot analysis of histones isolated from Drosophila S2 cells treated with Scriptaid analogs 34, 31 , and 32. H2B detection was used to ensure equivalent protein loading to each well. Dark bottom bands most prominent in lanes 4,5 and 7 indicate the enhanced abundance of tetra-AcLys H4, consistent with HDAC inhibition by 31 and 32. Lane 1 is a dioxane solvent control and concentrations of "drug" in cell medium are indicated above each lane. All cells were treated for a period of 48 hours at ambient temperature prior to nuclei isolation and processing.
  • Lanes 1 and 4 correspond to histone isolated from cells treated with 27, which lacks any pharmacophore moiety but retains the synthetically useful TBDPS moiety which, from the biological perspective, serves as a "cap” group. Importantly, cells treated with 27 rendered little acetylated H4 as reflected by little or no chemiluminescent signal upon use of a horseradish peroxidase secondary antibody. Conversely, cells subjected to both
  • RNA interference RNA interference
  • Drosophila S2 cells may be subjected to the proposed agents.
  • Media is supplemented with varying concentrations of exogenous oxidoreductases (with accompanying cofactors) and cells grown for periods ranging from 1 2 to 96h.
  • Cell lysis is conducted and then histone analyses performed as previously described. Changes in histone acetylation status are ascertained via Western blots and these results contrasted with those derived using cell-free lysate.
  • An alternative, albeit secondary approach is to generate S2 cells that overexpress deadhead (dhd), the gene which encodes the Drosophila homolog of human thioredoxin (Pellicena-Palle et al., 1 997, Mech. Dev. 62: 61 -65).
  • Trx ⁇ s also overexpressed in gastric carcinomas; this overexpression has been linked to the development of cisplatin, mitomycin C, anthracycline and etoposide resistance (Becker et al., 2000, Eur. J. Biochem. 267: 61 1 8-61 25). It is therefore highly significant that Richon and co-workers have demonstrated that SAHA (5)) down regulates Trx ' m human primary breast and colon tumor tissues (Butler et al., 2002, Proc. Natl. Acad, Sci. USA 99: 1 1 700-1 1 705). It is unclear if SAHA will exert similar effects upon normal mammalian cells in which Trx plays a vital role in maintaining cellular redox levels compatible with DNA synthesis (via ribonucleotide reductase), transcription factor activity and the like.
  • lactones of the type 86 can be readily converted to their TBS silyl ether counterparts which are transformed to acetylthiols of generically depicted by 87.
  • Deacetylation is readily accomplished with NaOMe although dissolving metal reduction of the S-benzyl moiety might proceed with concomitant deacetylation. In either event, generation of 89 is likely to proceed with high yields. Numerous opportunities exist for generation of the disulfide 90. Generation of bis(tri-n-butyltin) thiolates followed by subjection to either 12 or Br2 affords cyclic disulfides in very respectable yields.
  • ring sizes ⁇ 7 are formed in ⁇ 80% yield; for ring sizes of 8 or greater disulfides are generated in ⁇ 50% yield (Harpp et al., 1 986, Tet. Lett. 27: 441 -444). This fares extremely well against alternative means of cyclic disulfide generation.
  • conditions reported by Zoller and co-workers can be used (Zoller et al., 2000, Tet. Lett. 41 : 9989-9992). Reaction of 86 with dimethylsulfide and N-chlorosuccinimide affords an activated dimethylsulfonium which readily reacts with S-benzyl thioethers to give the debenzylated disulfide.
  • This chemistry is applicable to compounds with ring sizes ranging from 6 to 1 4 and is compatible with peptidic substrates. Following disulfide generation, desilylation will be performed thus rendering the hydroxymethyl moiety again, as a handle by which to attach diverse cap structures.
  • the present invention also teaches a highly efficient method for the construction of cyclic disulfides based on the synthesis of differentially protected dithiols.
  • This method inspired by Simon's original total synthesis of FK228, calls for production of 1 24a-d (two steps from commercially available materials) followed by ⁇ -mediated disulfide installation.
  • bromoacids of form 1 21 bearing 3,4,5, and 6 methylene units are commercially available and the inventors have already shown that the chemistry in Figure 6b works very efficiently to generate substances like 1 24 following carbonyldiimidazole (CDI)-mediated amide bond formation with S-Trt cysteine methyl ester 1 23.
  • CDI carbonyldiimidazole
  • the ditritylated methyl esters of form 1 24 undergo very clean conversion to macrocycles of kind 125.
  • the inventors have successfully produced agents 1 25b-d using this high yielding method. Further, the inventors have found that 1 25b is amenable to LiBH4 reduction to render 1 26b; this chemistry should be applicable to materials 126a, 1 26c and 1 26d as well.
  • the hydroxymethyl group of all 1 26 agents provides one of two possible handles by which to attach appropriate capping groups of interest.
  • the inventors have also successfully saponified methyl esters 1 25b-d to afford acids 1 27b-d; the inventors believe 127a will also be achievable using this base-catalyzed hydrolysis.
  • Agents of the type 1 27 are important since the carboxylic acid is readily coupled to a wide assortment of amine-bearing cap groups.
  • the inventors have found CDI to be a very effective agent.
  • the panel of amino bearing cap groups will facilitate rapid construction and assaying for a wide array of cyclic disulfides with a high likelihood for HDAC inhibitory activity.
  • Oxazoline formation constitutes ⁇ 10-20% of the obtained product from such couplings.
  • the cyclic nature of 79 - 82 abrogates oxazoline formation, instead favoring the desired "capped" products.
  • a “targeting agent” may be any substance (such as a compound) that, when associated with an analog of FK228 enhances the local concentration of the analog at a target tissue.
  • [Para 1 1 1 ]Targeting agents include, in addition to capping structures described elsewhere, antibodies or fragments thereof, receptors, ligands and other molecules that bind to cells of, or in the vicinity of, the target tissue.
  • Known targeting agents include serum hormones, antibodies against cell surface antigens, lectins, adhesion molecules, tumor cell surface binding ligands, steroids, cholesterol, lymphokines, fibrinolytic enzymes and those drugs and proteins that bind to a desired target site.
  • an antibody targeting agent may be an intact (whole) molecule, a fragment thereof, or a functional equivalent thereof.
  • antibody fragments are F(ab')2, -Fab', Fab and F[v] fragments, which may be produced by conventional methods or by genetic or protein engineering.
  • Linkage is generally covalent and may be achieved by, for example, direct condensation or other reactions, or by way of bi- or multifunctional linkers.
  • a polynucleotide encoding a modulating agent may also be possible to target a polynucleotide encoding a modulating agent to a target tissue, thereby increasing the local concentration of modulating agent, e.g. thioredoxin, thioredoxin reductase or other reductive enzymes.
  • modulating agent e.g. thioredoxin, thioredoxin reductase or other reductive enzymes.
  • Such targeting may be achieved using well known techniques, including retroviral and adenoviral infection, as described above.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1 ) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; or (4) intravaginally or intrarectally, for example, as a pessary, cream patches or foam.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
  • parenteral administration for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a deacetylase inhibitor of the present invention which is effective for producing some desired therapeutic effect by inhibiting histone deacetylation in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that event in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject deacetylase inhibitor agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject deacetylase inhibitor agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically- acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (1 0) glycols, such as propylene glycol; (1 1 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (1 2) esters, such as ethyl oleate and ethyl laurate; (1 3) agar; (1 4) buffering agents, such as water
  • certain embodiments of the present deacetylase inhibitors may contain a basic functional group, such as amino or alkyl amino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1 977) "Pharmaceutical Salts", J Pharm. Sci. 66: 1 -1 9)
  • the deacetylase inhibitory compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically- acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically- acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
  • antioxidants examples include: (1 ) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the deacetylase inhibitor which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 1 0 per cent to about 30 per cent.
  • compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a deacetylase inhibitor of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a deacetylase inhibitor of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered deacetylase inhibitor moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the deacetylase inhibitors of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active deacetylase inhibitor, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active deacetylase inhibitor.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active deacetylase inhibitor.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a deacetylase inhibitor of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active deacetylase inhibitor of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the deacetylase inhibitor in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the deacetylase inhibitor across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the deacetylase inhibitor in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral administration comprise one or more deacetylase inhibitors of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium cWoride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium
  • Injectable depot forms are made by forming microencapsule matrices of the subject deacetylase inhibitors in biodegradable polymers such as polylactide- polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • the deacetylase inhibitor may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular deacetylase inhibitor employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular deacetylase inhibitor employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • the compounds of the present invention are likely to play an important role in the modulation of cellular proliferation.
  • pathological cell proliferative conditions for which therapeutics of the present invention may be used in treatment.
  • such agents can provide therapeutic benefits where the general strategy being the inhibition of an anomalous cell proliferation.
  • Diseases that might benefit from this methodology include, but are not limited to various cancers and leukemias, psoriasis, bone diseases, fibroproliferative disorders such as involving connective tissues, atherosclerosis and other smooth muscle proliferative disorders, as well as chronic inflammation.
  • the present invention contemplates the use of therapeutics for the treatment of differentiative disorders which result from, for example, de-differentiation of tissue which may (optionally) be accompanied by abortive reentry into mitosis, e.g. apoptosis.
  • degenerative disorders include chronic neurodegenerative diseases of the nervous system, including Alzheimer's disease, Parkinson's disease, Huntington's chorea, amylotrophic lateral sclerosis and the like, as well as spinocerebellar degenerations.
  • disorders associated with connective tissue such as may occur due to de-differentiation of chondrocytes or osteocytes, as well as vascular disorders which involve de-differentiation of endothelial tissue and smooth muscle cells, gastric ulcers characterized by degenerative changes in glandular cells, and renal conditions marked by failure to differentiate, e.g. Wilm's tumors.

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Abstract

Analogues de FK228 et méthodes de production et d'utilisation desdits analogues. Ces analogues sont de puissants inhibiteurs de l'histone désacétylase et, dans certains modes de réalisation, sont capables de cibler spécifiquement des cellules et tissus cancéreux. Dans des modes de réalisation préférés, ces analogues sont caractérisés par un motif disulfure cyclique.
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