WO2012126084A1 - Composés de liaison à hsp-90, compositions de ces composés, et utilisations de ces composés pour le traitement et la prévention d'infections fongiques - Google Patents

Composés de liaison à hsp-90, compositions de ces composés, et utilisations de ces composés pour le traitement et la prévention d'infections fongiques Download PDF

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WO2012126084A1
WO2012126084A1 PCT/CA2011/050158 CA2011050158W WO2012126084A1 WO 2012126084 A1 WO2012126084 A1 WO 2012126084A1 CA 2011050158 W CA2011050158 W CA 2011050158W WO 2012126084 A1 WO2012126084 A1 WO 2012126084A1
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compound
attorney docket
mmol
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PCT/CA2011/050158
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Patrick Bureau
Jean-Hugues Fournier
James B. Jaquith
Alain Laurent
Yannick Rose
Mélanie PROULX
Stephen Morris
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Pharmascience Inc.
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Priority to PCT/CA2011/050158 priority Critical patent/WO2012126084A1/fr
Publication of WO2012126084A1 publication Critical patent/WO2012126084A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the heat shock protein 90 family including HSP90 alpha, HSP90 beta, HSP90 N, GRP94 and TRAP-1 (herein generically referred to as HSP90), are essential molecular chaperones that participate in folding of newly synthesized proteins and stabilization and refolding of stress-denatured client proteins.
  • HSP90 client proteins A large number of HSP90 client proteins have been identified many of which are involved in cellular signaling. Consequently, inhibition of HSP90 is widely regarded as a promising therapeutic approach for the treatment of diseases and conditions characterized by inappropriate cellular signaling and stress responses including cancer, neurodegeneration, inflammation and autoimmune disease. Additionally, the use of HSP90 inhibitors in the inhibition of fungal and parasitic infections is expected to be a useful approach to treating pathogenic fungal and parasitic infections.
  • HSP90 and analogues are relatively large proteins that have characteristic Bergerat ATP binding folds and belong to the GHKL protein superfamily of ATPases and protein kinases (Dutta, R. and Inouye, M., Trends Biochem Sci., 2000, 25( 1): 24-8). Crystallography studies revealed a pocket in the N-terminal domain with sequence homology to type II topoisomerases and MutL mismatch repair proteins which co-crystallized with ATP/ADP and established that the N-terminal region is a binding site for adenine nucleotides
  • HSP90 has a middle segment that participates in client protein binding and a c-terminal domain that is responsible for dimerization and binding of some natural products including novobiocin (Pearl, L. H. and Prodromou, C, Annu Rev Biochem, 2006, 75: 271-94).
  • HSP90 is one of the most abundant cellular proteins comprising 1-2% of total cellular protein (Iwasaki, M. et al., Biochim Biophys Acta, 1989, 992(1): 1-8). HSP90 alpha and HSP90 beta are dimeric cytosolic proteins whereas GRP94 and TRAP- 1 reside in the endoplasmic reticulum and mitochondria respectively. HSP90 binds to a series of co- chaperones in an ATP dependent manner, thereby modulating the structure of client proteins.
  • HSP90 exerts its cellular function through selectively chaperoning, or promoting conformational changes and domain rearrangements in a wide range of client proteins including nuclear hormone receptors (Pratt, W. B. and Toft, D. O., Exp Biol Med (Maywood), 2003, 228(2): 1 1 1-33) and protein kinases (Pearl, L. H., Curr. Opin. Genet. Dev., 2005, 15(1): 55-61).
  • Pharmacological inhibition of HSP90 results in induction of a heat shock response as well as destabilization of HSP90 client proteins. In contexts where pathology is driven by proteins that are HSP90 clients it is expected that HSP90 inhibition will result in destabilization of key proteins leading to therapeutic benefit.
  • HSP70 heat shock protein 70
  • induction of a heat shock response including enhanced synthesis of heat shock protein 70 (HSP70) (Lu, A. et al., J. Neurochem., 2002, 81 (2): 355-64), following inhibition of HSP90, may protect normal cells from inappropriate toxicity.
  • HSP70 heat shock protein 70
  • the present inventors teach a novel class of HSP90 inhibitors that demonstrate antifungal activity as single agents and in combination with standard anti-fungal agents such as
  • the invention relates to compounds having a structure of Formula 1 , or a pharmaceutically acceptable salt thereof
  • A is selected from Al an
  • each X is independently selected from CR and N, preferably selected such that no more than two occurrences, and more preferably no more than one occurrence, of X are N;
  • R is selected from -CN and C(0)NH 2 ;
  • R 1 is NH 2 ;
  • each R is independently selected from hydrogen halogen, -N0 2 , -CN, alkyl, alkenyl, alkynyl, -OR 3 , -NR 4 R 5 , -S(0) m R 3 , -C(0)R 3 , -C(0)OR 3 , -C(0)NR 4 R 5 , -S(0) 2 NR 4 R 5 , aryl, heteroaryl, carbocyclyl, and heterocyclyl;;
  • each R ⁇ R 4 , and R ⁇ is independently selected from hydrogen, -alkyl-R 6 , carbocyclyl, heterocyclyl, heteroaryl, and aryl; or
  • R 4 and R ⁇ together are alkylene, thereby forming a ring
  • R 6 is selected from hydrogen, hydroxy, alkoxy, -NHC(0)alkyl, -NHSC ⁇ alkyl, amino, and heterocyclyl;
  • n is an integer from 0 to 2;
  • D is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
  • E is selected from carbocyclyl and heterocyclyl.
  • the invention relates to pharmaceutical compositions comprising a compound of Formula 1 and a pharmaceutically acceptable carrier or diluent.
  • the invention relates to methods for the treatment of a disease or condition selected from fungal infection comprising administering a compound of Formula 1.
  • Figure 1 is a graph showing HSP90 inhibitors block growth of Candida albicans and synergize with Fluconazole and Caspofungin
  • Figure 2 is a graph showing HSP90 inhibitors are fungocidal alone and in combination with Fluconazole and Caspofungin.
  • Figure 3 is a graph showing plasma levels of compound 34 in mice dosed with 100 mg/kg compound 34 formulated in cremophor ELP by oral route.
  • the invention relates to compounds having a structure of Formula 1 , or a pharmaceutically acceptable salt thereof
  • A is selected from Al (wherein 1-6 and 1-8, respectively refer to positions on the ring);
  • each X is independently selected from CR and N;
  • R is selected from -CN and -C(0)NH 2 ;
  • R 1 is NH 2 ;
  • each R is independently selected from hydrogen, halogen, -N0 2 , -CN, alkyl, alkenyl, alkynyl, -OR 3 , -NR 4 R 5 , -S(0) m R 3 , -C(0)R 3 , -C(0)OR 3 , -C(0)NR 4 R 5 , -S(0) 2 NR 4 R 5 , aryl, heteroaryl, carbocyclyl, and heterocyclyl;
  • each R ⁇ R 4 , and R ⁇ is independently selected from hydrogen, -alkyl-R 6 , carbocyclyl, heterocyclyl, aryl and heteroaryl; or
  • R 4 and R ⁇ together are alkylene, thereby forming a ring
  • R 6 is selected from hydrogen, hydroxy, alkoxy, -NHC(0)alkyl, -NHS0 2 alkyl, amino, and heterocyclyl;
  • n is an integer from 0 to 2;
  • D is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
  • E is selected from carbocyclyl and heterocyclyl.
  • A is Al , wherein each occurrence of X is independently CR In certain alternative embodiments, A is Al , wherein one or two occurrences of X are
  • Al is CR 2 , R 2 is other than hydrogen.
  • X 1 is CR 2 wherein R 2 is -NR 4 R ⁇ R 4 is hydrogen and R ⁇ is carbocyclyl or heterocyclyl.
  • X 1 is CR 2 wherein R 2 is -NR 4 R ⁇ R 4 is hydrogen and R ⁇ is heterocyclyl.
  • X 1 is CR 2 wherein R 2 is -NR 4 R ⁇ R 4 is hydrogen and R ⁇ is carbocyclyl-R 7 wherein
  • R 7 is selected from -OR 14 , -NR I2 R 13 , -C(0)NR l2 R 13 , -S0 2 NR l2 R 13 ,
  • each R 12 and R 1 1 is independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; or
  • R 12 and R 1 1 together form a substituted or unsubstituted heterocyclyl ring system; and R l4 and R 15 are selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl.
  • the carbocyclyl group of carbocyclyl-R is a trans 1-4 disubstituted 6-membered ring.
  • the carbocyclyl group of carbocyclyl-R is a six-membered ring.
  • R is preferably located at the 4- position of the carbocyclyl ring relative to the point of attachment to A.
  • R is hydrogen and R is carbocyclyl-R , other occurrences of R in Formula 1 are independently selected from hydrogen or halogen.
  • R 4 is hydrogen and R ⁇ is heterocyclyl, other occurrences of R 2 in Formula 1 are
  • A is selected from
  • A is A2, wherein each occurrence of X is independently CR . In certain embodiments, A is A2, wherein one or two occurrences of X are N.
  • the R 2 attached to X 6 , X 7 , or X 8 preferably the R 2 attached to X of A2 is other than hydrogen.
  • R 2 is selected from hydrogen, halogen, -CN, alkyl, -OR ⁇ - NR 4 R ⁇ -S(0) m R J , and -C(0)NR 4 R ⁇ In certain such embodiments, R 2 is selected from hydrogen and NR 4 R ⁇
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • X 6", X 7', or X 8° is CR 2 more preferably when X 8 is CR 2 , is selected from alkyl, halogen, -OR 3 , and -S(0) m R ⁇
  • R 2 is alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • at least one occurrence of R is halogen, preferably Br or F.
  • At least one occurrence of R 2 are -OR ⁇ In certain such embodiments, R 2 is selected from - 0(CH 2 ) 2 OCH 3 , -0(CH 2 ) 2 N(CH 3 ) 2 , -0(CH 2 ) 2 OH, and OEt. In certain alternative such embodiments, at least one occurrence of R 2 is -S(0) m R ⁇ In certain such embodiments, R 2 is selected from
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • Q is selected from -C(O)-, and -S(0) n -; and n is an integer from 1 to 2.
  • D is aryl or heteroaryl, preferably phenyl, pyridyl, thienyl, thiazolyl, oxazole, or isoxazole.
  • D is carbocyclyl, preferably cyclopentyl or cyclohexyl.
  • B is selected from
  • B is selected from
  • B is selected such that the D ring is one of the D rings specified in the previous paragraph and the E ring is one of the E rings specified in the paragraph prior to that.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula 1 and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the present invention provides a method of treating a proliferative disorder or a disease state, the method comprising administering to a subject in need thereof an amount of a compound or pharmaceutical composition as described above sufficient to treat the proliferative disorder or disease state.
  • Another aspect of the present invention provides a method of modulating HSP function, the method comprising contacting a cell with a compound of the present invention in an amount sufficient to modulate the binding of a HSP client protein to HSP, thereby modulating the HSP function.
  • Another aspect of the present invention provides a method of modulating HSP function, the method comprising contacting a cell with a compound of the present invention in an amount sufficient to modulate HSP90 function affecting protein folding, stability and aggregation.
  • the invention relates to methods for the treatment of a disease or condition selected from the treatment of fungal infections.
  • pathogenic fungal infections include species of: Candida, Aspergillus, Cryptococcus, Trichophyton, Microsporum, Epidermophtyon, and Malassezia.
  • Infections which may be treated with compounds of the instant invention include: Candida albicans, Aspergillus fumigatus, Aspergillus terreus, Trichophyton rubrum and Cryptococcus neoformans.
  • Compounds of the instant invention may be used to treat fungal infections anywhere in the body including vaginal, dermal, nail, meningial, as well as systemic infections.
  • Compounds of the instant invention may be used for the treatment of fungal infections either alone or in combination with other agents used in the treatment or prophylaxis of fungal infections.
  • Table 1 summarizes therapeutic agents used in the treatment of fungal infections and is provided to be illustrative of potential
  • Compounds prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art.
  • the compounds may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular, or subcutaneous), drop infusion preparations, or suppositories.
  • injections intravenous, intramuscular, or subcutaneous
  • drop infusion preparations or suppositories.
  • ophthalmic mucous membrane route they may be formulated as eye drops or eye ointments.
  • the active ingredient may be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and/or a buffer.
  • a binder such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and/or a buffer.
  • a daily dosage from 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses.
  • the amount of active ingredient which can be combined with a carrier material to produce a
  • physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc.
  • the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication,
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • 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 corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrin; (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, corn oil, and soybean oil; ( 10) glycols, such as propylene glycol; ( 1 1) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; ( 12) esters, such as ethyl oleate and ethyl
  • compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) 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, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate naphthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming
  • “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) 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.
  • 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).
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening,
  • 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 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 matrix, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes, and the like, each containing a predetermined amount of a compound(s) as an active ingredient.
  • a composition may also be administered as a bolus, electuary, or paste.
  • solid dosage forms for oral administration capsules, tablets, pills, dragees, powders, granules, and the like
  • 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, cyclodextrins, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
  • compositions may also comprise buffering agents.
  • 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 compound(s) moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms 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. They 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.
  • 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.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration 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,
  • 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 compound(s), 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 for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compound(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, 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 agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, 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 agent.
  • Formulations 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 compound(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required or beneficial.
  • the ointments, pastes, creams, and gels may contain, in addition to compound(s), 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(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the compound(s) can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the composition.
  • a nonaqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular composition, but typically include nonionic surfactants (Tweens, Pluronics, sorbitan esters, lecithin, Cremophors), pharmaceutically acceptable co-solvents such as polyethylene glycol, innocuous proteins like serum albumin, oleic acid, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound(s) across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound(s) in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral administration comprise one or more compound(s) in combination with one or more pharmaceutically acceptable sterile 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,
  • 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 tonicity-adjusting agents, such as sugars, sodium chloride, 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 tonicity-adjusting agents, such as sugars
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms can be made by forming microencapsulated matrices of compound(s) 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.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • agents 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, infusion; topically by lotion or ointment; and rectally by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial,
  • systemic administration means the administration of a ligand, drug, or other material other than directly into the central nervous system, such that it enters the patient's system and thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compound(s) 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 compound(s), 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.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • compositions of this invention may be provided in an aqueous solution containing about 0.1 -10% w/v of a compound disclosed herein, among other substances, for parenteral administration. Typical dose ranges are from about 0.01 to about 50 mg/kg of body weight per day, given in 1-4 divided doses. Each divided dose may contain the same or different compounds of the invention.
  • the dosage will be an effective amount depending on several factors including the overall health of a patient, and the formulation and route of administration of the selected compound(s).
  • affinity tag means a ligand or group, linked either to a compound of the present invention or to an HSP domain, that allows the conjugate to be extracted from a solution.
  • alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, cyclopropylmethyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkenyl and alkynyl refer to substituted or unsubstituted 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.
  • Representative alkenyl groups include vinyl, propen-2-yl, crotyl, isopenten-2-yl, l ,3-butadien-2-yl), 2,4-pentadienyl, and l ,4-pentadien-3-yl.
  • alkynyl groups include ethynyl, 1- and 3-propynyl, and 3-butynyl.
  • alkyl substituents are lower alkyl groups, e.g., having from 1 to 6 carbon atoms.
  • alkenyl and alkynyl preferably refer to lower alkenyl and alkynyl groups, e.g., having from 2 to 6 carbon atoms.
  • alkylene refers to an alkyl group with two open valencies (rather than a single valency), such as -(CH 2 )i-io- and substituted variants thereof.
  • alkoxy refers to an alkyl group having an oxygen attached thereto.
  • alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxy.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, thereby forming an ether.
  • amide and “amido” are art-recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R 9 , R 10 are as defined above.
  • Preferred embodiments of the amide will not include imides, which may be unstable.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by the general formulae:
  • R 9 , R l() and R l() each independently represent a hydrogen, an alkyl, an
  • R 9 and R l() taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and
  • m is zero or an integer from 1 to 8.
  • only one of R 9 or R 10 can be a carbonyl, e.g., R 9 , R l() , and the nitrogen together do not form an imide.
  • R 9 and R l() each independently represent a hydrogen, an alkyl, an alkenyl, or - (CH 2 ) m -R ⁇
  • the amino group is basic, meaning the protonated form has a pK a > 7.00.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein includes 5-, 6-, and 7-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, anthracene, and phenanthrene.
  • carbocycle and “carbocyclyl”, as used herein, refer to a non-aromatic substituted or unsubstituted ring in which each atom of the ring is carbon.
  • the terms “carbocycle” and “carbocyclyl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is carbocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Representative carbocyclic groups include cyclopentyl, cyclohexyl, 1-cyclohexenyl, and 3- cyclohexen- l-yl, cycloheptyl.
  • carbonyl is art-recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • R 1 1 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R or a pharmaceutically acceptable salt.
  • X is an oxygen and R 1 1 is not hydrogen
  • the formula represents an "ester”.
  • X is an oxygen, and R 1 1 is a hydrogen
  • the formula represents a "carboxylic acid”.
  • heteroaryl includes substituted or unsubstituted aromatic 5- to 7- membered ring structures, more preferably 5- to 6-membered rings, whose ring structures include one to four heteroatoms.
  • heteroaryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, isoxazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl or “heterocyclic group” refer to substituted or unsubstituted non-aromatic 3- to 10-membered ring structures, more preferably 3- to 7-membered rings,
  • heterocyclyl or “heterocyclic group” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, tetrahydrofuran, piperidine, piperazine, pyrrolidine, morpholine, lactones, and lactams.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • polycyclyl or “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings".
  • rings e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an
  • the term "probe” means a compound of the invention which is labeled with either a detectable label or an affinity tag, and which is capable of binding, either covalently or non-covalently, to an HSP domain.
  • the probe When, for example, the probe is non- covalently bound, it may be displaced by a test compound.
  • the probe When, for example, the probe is bound covalently, it may be used to form cross-linked adducts, which may be quantified and inhibited by a test compound.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or
  • substituted with includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched,
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by
  • hydrocarbon chain can themselves be substituted, if appropriate.
  • treating includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition.
  • the term "well tolerated” refers to a substance, such as a
  • orally bioavailable refers to a substance, such as a pharmaceutical compound or composition, that can be taken orally for therapeutic efficacy.
  • Compounds of the invention also include all isotopes of atoms present in the intermediates and/or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Intermediate 1-d may be prepared by reacting o-alkynyltrifluoroacetanilide intermediate 1-d with aryl halide 1-e in the presence of a ligand, a catalyst and a base.
  • intermediate 1-f Treatment of intermediate 1-f with an appropriate base provides intermediate 1-g. Cyclized intermediate 1-g can also be obtained from intermediate 1-d in a one step-method under suitable conditions. Treatment of intermediate 1-g with an amine of formula R 4 R 5 NH provides intermediate 1 -h. Nitrile hydrolysis of intermediate 1-h provides compounds of formula 1.
  • Intermediates 2-c may be prepared by reacting o-alkynyltrifluoroacetanilide intermediates 1-d with aryl halide 2-b in the presence of a ligand, a catalyst and a base.
  • intermediate 1-a Treatment of intermediate 1-a, preferentially a chlorine derivative, with intermediate 1-b afford intermediate 3-a.
  • Sonogashira coupling reaction of aryl halide 1 -e with terminal alkyne intermediate 3-a provides intermediate 3-b.
  • Treatment of intermediate 3-b with an appropriated base, ligand and catalyst provides polycyclic intermediate 1-g.
  • intermediate 10-b (3.0 g, 19.45 mmol) in EtOH was added 4- methylbenzenesulfonohydrazide (3.62 g, 19.45 mmol) and the reaction was then stirred at room temperature for 20 minutes and 55 °C for 2 hours. Water and CH 2 CI 2 were added; the organic layer was separated, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo to provide intermediate 10-c as colorless oil.
  • intermediate 10-d 600 mg, 4.28 mmol
  • MeOH MeOH
  • acetyl chloride 304 uL, 4.28 mmol
  • the reaction was then stirred at 40 °C for 2 hours.
  • Water and CH 2 CI 2 were added, the organic layer was separated, the aqueous phase was extracted with CH 2 CI 2 , and the combined organic layer was separated, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo to provide intermediate 10-e as yellow oil.
  • intermediate 20-b (3.63 g, 12.73 mmol) in DCM cooled to 0°C were sequentially added imidazole (1.04 g, 15.27 mmol) and fcrf-butylchlorodimethylsilane (2.1 1 g, 14.0 mmol) and the reaction was then stirred at room temperature overnight. Water and ethyl acetate were added; the organic layer was separated, washed with 10% citric acid, saturated NaHCO:, and brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 20-c as a yellow oil.
  • intermediate 21-d To a suspension of intermediate 21-d (357 mg, 1.79 mmol) and 4-bromo-2,6- diflurobenzonotrile (391 mg, 1.79 mmol) in DMSO was added TEA (553 uL, 3.94 mmol) and the reaction was then stirred at room temperature for 2 days. Saturated aqueous ammonium chloride and ethyl acetate were added; the organic layer was separated, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 21-f as a white solid.
  • intermediate 1 1 -a (1.65 g, 6.66 mmol) in DMSO were sequentially added TEA (2.80 mL, 19.97 mmol) and 4-aminothiomorpholine 1, 1 -dioxide ( 1.0 g, 6.66 mmol) and the mixture was then heated at 130°C for 7 days and then cooled to room temperature. Saturated aqueous ammonium chloride and ethyl acetate were added, the organic layer was separated, washed with brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 29-a as a beige solid.
  • intermediate 30-e (1.21 g, 4.0 mmol) in DCM cooled to 0°C were sequentially added DIPEA (2.80 mL, 16.06 mmol) , DMAP (25 mg, 0.20 mmol) and TFAA (1.24 mL, 8.83 mmol) and the reaction was then stirred at room temperature for 4 hours. Water and ethyl acetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride, saturated aqueous NaHCO:, and brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 30-f as a beige solid.
  • intermediate 30-f 1.10 g, 2.75 mmol
  • intermediate 30-c 821 mg, 2.62 mmol
  • Cs 2 C0 3 (1.28 g, 3.93 mmol
  • Pd(PPh 3 ) 4 91 mg, 0.08 mmol
  • the reaction was stirred at 120°C overnight and then cooled to room temperature.
  • Water and ethylacetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride, dried over anhydrous MgS0 4 , filtered and
  • intermediate 31-c (2.60 g, 8.09 mmol) in DCM cooled to 0°C were sequentially added DIPEA (5.65 mL, 32.4 mmol) , DMAP (49 mg, 0.40 mmol) and TFAA (2.51 mL, 17.80 mmol) and the reaction was then stirred at room temperature for 2 hours. Water and ethyl acetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride, saturated aqueous NaHCO:, and brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 31-d as a yellow oil.
  • intermediate 33-b (1.20 g, 4.21 mmol) in DMSO/MeOH ( 1 : 1 , 84.2 mL) was sequentially added NaOH IN (4.21 mL, 4.21 mmol) and 30% aqueous hydrogen peroxide (645 uL, 6.31 mmol) and the reaction was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added; the organic layer was separated, washed with brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Hexane was added and intermediate 33-b was collected by filtration as an off-white solid.
  • Fluorescence polarization based HSP90 binding assay was performed using modifications to previously described methods using full length HSP90 and a geldanamycin- FITC probe (see Llauger-Bufi, L. et al., Bioorg. Med. Chem. Lett. 13 (2003) 3975-3978).
  • geldanamycin-FITC probe was diluted into HFB buffer [20 mM HEPES (K) pH 7.3, 50 mM KC1, 1 mM DTT, 5 mM MgCl 2 , 20 mM Na 2 Mo0 4 , 0.01 % NP40, 0.1 mg/mL of Bovine gamma-globuline] to obtain a working concentration of 8 nM.
  • HSP90 protein Hsp90 Native Protein, Stressgen, SPP-770
  • the final amount of protein used in the assay corresponds to the amount of protein necessary to obtain 80% of the maximum FP value in a 2 nM probe saturation experiment.
  • Assay were carried out in duplicates, into not treated black 96-well plate (Corning #3915), in a total volume of 100 ⁇ , for a final concentration of 2 nM of geldanamycin-FITC probe, various concentrations of compound and Hsp-90 protein into HFB buffer. Buffer only (blank) or probe only in buffer (G-factor) were also added to be used as controls for calibration. The plate was left on a shaker at 4 °C for 3 hours and the FP values in mP were recorded using Genios Pro FP reader (TECAN).
  • the measured FP values were then plotted against compound concentration and EC 50 , corresponding to the competitor concentrations where 50% of the tracer was displaced, calculated based on a sigomoidal dose-response (variable-slope) curve fit using GraphPad Prism version 4.02 for Windows, GraphPad Software, San Diego California USA, www.graphpad.com.
  • IC 50 A less than 100 nM; B between 100 and 1000 nM; C greater than 1000 nM.
  • Anti-fungal activity was determined in vitro by incubation of Candida albicans cultures with serial two fold dilutions of HSP90 inhibitors alone or in combination with serial two fold dilutions of fluconazole or caspofungin. Fungal growth was measured by absorbance at 600 nM ( Figure 1).
  • Fungicidal activity was demonstrated by plating cells from the above liquid cultures on solid media in the absence of HSP90 inhibitor, fluconazole or caspofugin and allowing fungal growth to occur before photography (Figure 2).
  • Figure 1 shows that HSP90 inhibitors block growth of Candida albicans and synergize with Fluconazole and Caspofungin.
  • Candida albicans cultures were treated with 2 fold dilutions of compound 34 or compound 1 17 in combination with 2 fold dilutions of either fluconazole or caspofungin. Cell growth was determined by light absorbance.
  • FIG. 2 shows that HSP90 inhibitors are fungocidal alone and in combination with
  • Candida albicans cultures were treated with 2 fold dilutions of compound 1 17 or compound 34 in the absence of drug or in the presence
  • the PK of compounds of formula 1 were determined in the plasma of mice after treating CD-I mice with compound via IV or oral administration.
  • Compound concentrations were determined using acetonitrile extraction of compound from the appropriate matrix and calculation of drug concentrations using a spiked standard curve from the same matrix (ie. plasma).
  • Figure 3 shows the plasma levels of compound 34 in mice dosed with 100 mg/kg compound 34 formulated in cremophor ELP by the oral route. Data indicate that oral administration to mice can deliver active concentrations of compound to plasma. Following oral dosing exposure of compound 34 was in excess of 2 uM which is above the

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Abstract

L'invention concerne des composés thérapeutiques qui se lient à HSP90. Lesdits composés se lient à HSP90 et modifient la capacité de chaperonnage des protéines HSP90. L'invention concerne également des compositions pharmaceutiques qui comprennent lesdits composés, ainsi que des méthodes de traitement ou de prévention d'infections fongiques.
PCT/CA2011/050158 2011-03-24 2011-03-24 Composés de liaison à hsp-90, compositions de ces composés, et utilisations de ces composés pour le traitement et la prévention d'infections fongiques WO2012126084A1 (fr)

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WO2023077216A1 (fr) * 2021-11-02 2023-05-11 Bright Angel Therapeutics Inc. Inhibiteurs de la protéine de choc thermique 90 (hsp90) pour le traitement d'infections fongiques et leurs procédés d'utilisation

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