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WO2006081659A1 - Inhibiteurs meroterpenoides de la phosphoinositide 3 kinase (pi3k) - Google Patents

Inhibiteurs meroterpenoides de la phosphoinositide 3 kinase (pi3k) Download PDF

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Publication number
WO2006081659A1
WO2006081659A1 PCT/CA2006/000131 CA2006000131W WO2006081659A1 WO 2006081659 A1 WO2006081659 A1 WO 2006081659A1 CA 2006000131 W CA2006000131 W CA 2006000131W WO 2006081659 A1 WO2006081659 A1 WO 2006081659A1
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Prior art keywords
compound
cho
liphagal
oso
carbon atoms
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Inventor
Raymond Andersen
Irwin Hollander
Deborah M. Roll
Steven C. Kim
Robert G. Mallon
David E. Williams
Frederic Marion
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University of British Columbia
Wyeth LLC
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University of British Columbia
Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the field of the invention relates to compounds having phosphoinositide 3-kinase (PI3K) inhibitory activity.
  • PI3K phosphoinositide 3-kinase
  • Phosphoinositide 3-kinase refers to a family of whose primary enzymatic activity is the phosphorylation of phosphoinositides, whereby different members of the kinase family generate different lipid products.
  • PI3 kinases have been implicated in numerous cellular processes, including proliferation, survival, adhesion, movement, differentiation, membrane trafficking, glucose transport, neurite outgrowth, super oxide production and cell signaling.
  • a key second messenger in the PI3K pathway is phosphatidylinostitol-3, 4,5-trisphosphate (PI-3,4,5-P 3 ), which is present at low concentrations in unstimulated cells, but is rapidly synthesized from PI-4,5-P 2 by PI3K in response to a wide array of extracellular stimuli.
  • Cells tightly regulate PI3K signaling by degrading PI-3,4,5-P 3 to PI- 4,5-P 2 with a tumor suppressor PTEN and to PI-3,4-P 2 with SHIP, sSHIP, or SHP2.
  • PTEN is a negative regulator of PI3K signaling and acts as a tumor suppressor gene which is prevalent in an estimated 50% of all human cancers.
  • PI3K has been found in numerous solid tumors such as colon, breast, ovarian and pancreatic cancers.
  • Samuels et al. (Science (2004) 304(5670):554) report the PIK3CA mutation in a number of cancer types including colon, brain, gastric, breast and lung cancers.
  • the PIK3CA gene encodes the pi 10a catalytic subunit of PI3K.
  • Nearly all of the PIK3CA mutations associated with colon cancer have been reported to be functionally active in carcinogenesis (Ikenoue T., et al. Cancer Research (2005) 65(ll):4562-7).
  • PIK3CA mutations have also been implicated in ovarian and breast carcinomas (Levine DA. et al. Clinical Cancer Research (2005) ll(8):2875-2878), and PIK3CA mutations have also been correlated with lymphnoid metastasis in human breast carcinoma (Saal LH. et al. Cancer Research (2005) 65(7):2554-2559. Lim K-H. and Counter CM. (Cancer Cell (2005) 8:381-392 has suggested an association between PI3K and Ras-driven human cancers. Ras has been associated with the initiation of tumorigenesis.
  • PB kinases can be divided into three main classes primarily on the basis of sequence homology, in vitro substrate preference and method of activation and regulation (Stein RC.
  • the Class Ia group consists of the classical pllO ⁇ and two additional closely related enzymes pi lO ⁇ and pi 105.
  • the pi 10 ⁇ and pi lO ⁇ isoforms are found through adult humans, whereas the pllO ⁇ is prominently expressed in the leukocytes, all of which are constitutively associated with p85 regulatory adaptor subunit to form a heterodimeric complex.
  • the sole member of Class IB is pi lO ⁇ whose expression is also confined largely to leukocytes, is associated with the plOl adaptor subunit.
  • Class 2 and Class 3 PI3 kinases are less well understood. As mentioned above, mutations in the pllO ⁇ gene have been associated with various cancers.
  • LY294002 (3) showed a dose dependent inhibition of tumor growth and decreased peritoneal and liver metastasis in a tumor xenograft mouse assay. Furthermore, it was shown that LY294002 (3) produced an additive inhibition of tumor growth when combined with suboptimal doses of gemcitabine.
  • Ng SSW. et al. (Cancer Research (2000) 60:5451-5455) have similarly shown that human pancreatic adenocarcinoma cells lines PKl and PK8, which are resistant to chemotherapy agent gemcitabine, when treated with PDK inhibitors (wortmannin (2) or LY294002 (3)) resulted in a concentration dependent enhanced apoptosis as compared with chemotherapy alone.
  • PBK inhibitors for example wortmannin (2) and its various analogs, LY294002 (3) and a synthetic analog of the flavenoid quercetin (4), have been widely used to elucidate the biological roles of PI3K signaling.
  • second generation isoform selective PI3K inhibitors whose structures are based on quercetin and LY294002 (3) have also been described in the patent literature (WO 01/81346, US 6,403,588 and U.S. 2003/0236271).
  • PI3K phosphoinositide 3 kinase
  • X 1 to X 4 are independently selected from: H, OH, OR, CHO, COR, CO 2 H, CO 2 R, OCOR, NH 2 , NHR, NR 2 , NO 2 , F, Cl, Br, I, OSO 3 H, SO 2 R, CN, SiR 3 and R; W is O, S, NH or NR;
  • a method of inhibiting the activity of a phosphoinositide 3 kinase comprising contacting a PI3K with a compound or salt thereof, the compound containing a heterocycle selected from:
  • X 1 to X 4 are independently selected from H, OH, OR, CHO, COR, CO 2 H, CO 2 R, OCOR, NH 2 , NHR, NR 2 , NO 2 , F, Cl, Br, I, OSO 3 H, SO 2 R, CN, SiR 3 and R;
  • W is O, S, NH or NR
  • R 1 is R;
  • the method wherein the compound is present in a pharmaceutically acceptable carrier.
  • the method wherein the compound is associated with a liposome.
  • the method wherein the compound is present as a pharmaceutically acceptable salt.
  • the method wherein the compound is liphagal, desformyl liphagal, desmethyl liphagal or deshydroxy-desformyl liphagal.
  • the method wherein the compound is an enantiomer having an absolute configuration of 5R, 8R, US.
  • the method wherein said contacting is in vivo.
  • the method wherein the contacting is in a human.
  • the method wherein said contacting is in vitro.
  • the method wherein an effective amount of the compound is provided to a subject in need thereof.
  • the method wherein the subject has a cancer treatable by inhibition of a PD K.
  • the method, wherein the PDK inhibited is PDK alpha.
  • composition including an isolated compound as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition wherein the compound is not listed in Table 3.
  • the composition for use in treating a cancer.
  • the use for treatment of a cancer in a subject The use, wherein the PDK is PDK alpha.
  • the PDK family of enzymes consists of several closely related isoforms that are thought to have different biological activities.
  • Small molecule drugs capable of attenuating PDK signalling, and in particular PDK isoform-selective modulation would have significant therapeutic potential for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases (Ward SG. et al. Chem. & Biol. (2003) 20:207-213; Ward SG. and Finan P. Current Opinion in Pharmacology (2003) 3:426-434; Wymann MP. et al Trends in Pharmacological Sciences (2003) 24:366-376; Yang L. et al Org. Lett. (2005) 7:1073-1076).
  • wortmannin (2) Two well-known first generation PDK inhibitors that have been widely employed as chemical genetics probes to elucidate the biological roles of PDK signaling are wortmannin (2) and LY294002 (3) are shown below in TABLE 1 adjacent Liphigal (1).
  • Wortmannin (2) a secondary metabolite of the fungus Penicillium wortmani, is a potent but nonselective inhibitor of PDKs.
  • LY294002 (3) is a synthetic analog of the flavanoid quercetin (4) (also shown below) and is considerably less potent than wortmannin, but shows much greater selectivity for PDK alpha versus PDK gamma.
  • siphonodictyal B (5) Frondosin B (6) isolated from Dysideafrondosa, and corallidictyals (7a) and (7b) isolated from A. coralliphagia.
  • AS-650240 is known to inhibit PDK (not shown C 22 H 2 oN 2 0 4 - CID 354242).
  • Liphagal (1) represents the first example of the 'liphagane' meroterpenoid carbon skeleton.
  • Liphigal (1) and analogues thereof described herein provide numerous PI3K inhibitors.
  • the present application also provides various synthesis schemes.
  • Scheme IA or IB shows two possible biogenetic routes to liphagal. Pathway A involves a proton initiated polyene cyclization of farnesylated trihydroxybenzaldehyde I with trapping of the intermediate carbocation by the ⁇ 2 3 olefin to give II, a putative intermediate in the biogenesis of siphonodictyal B (5).
  • Siphonodictyal B (5) could be converted to liphagal (1) via the epoxide III followed by ring expansion to ketone IV, epimerization at C- 8 and hemiketal formation to give V, and dehydration, ha pathway A, it is the 2' carbon of the prenyl residue that acts as a nucleophilic center in the polyene cyclization step.
  • the compounds shown in TABLE 2 are representative of compounds falling within the scope of the claimed novel compounds, wherein the definitions for R and X may be as follows.
  • X selected from any one of the following: H; CHO; OH; OR; COR; CO 2 H; CO 2 R; OCOR; NH 2 ; NHR; NR 2 ; NO 2 ; F; Cl; Br; OSO 3 H; SO 2 R; CN; or SiR 3 .
  • R selected from any one of the following: H; CHO; OH; OMe.
  • the compounds described herein may be formulated according to methods known to persons of skill in the art. Such formulations may include inactive precursor of the compounds described herein which are converted into their active form in the body by normal metabolic processes. Also included are metabolites of the compounds described herein.
  • Humans, and other animals, in particular, mammals, suffering from proliferative diseases, and other similar conditions may be treated by administering to the patient an effective amount of one or more of the above-identified pharmacophores or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, or subcutaneously.
  • salts or complexes refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal undesired toxicological effects.
  • Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount suffcient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • a preferred dose of the active compound for the above-mentioned conditions is in the range from about 0.5 to 500 mg/kg, preferably 1 to 100 mg/kg per day.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 1 to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dosage of 25-250 mg is usually convenient.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of about 0.1 to 100 ⁇ M, preferably about 1-10 ⁇ M. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient.
  • the concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose.
  • preferred carriers are physiological saline or phosphate buffered saline (PBS).
  • the active compound can also be administered through a transdermal patch.
  • Methods for preparing transdermal patches are known to those skilled in the art. For example, see Brown L., and Langer R., Transdermal Delivery of Drugs, Annual Review of Medicine, 39:221-229 (1988), incorporated herein by reference.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in US patent 4,522,811.
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine stearoyl phosphatidyl choline, arachadoyl phosphatidy choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, and/or triphosphate derivatives are then introduced into the container. The container is then swirled by hand to free the lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine stearoyl phosphatidyl choline, arachadoyl phosphatidy
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • Suitable pharmaceutically acceptable carriers for parenteral application include sterile water, physiological saline, bacteriostatic saline (saline containing 0.9 mg/ml benzyl alcohol) and phosphate-buffered saline.
  • the active compound or pharmaceutically acceptable salt or derivative thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active compound or pharmaceutically acceptable derivatives or salts thereof can also be administered with other active materials that do not impair the desired action, or with materials that supplement the desired action.
  • Zhu et al. (2006) supra teach a method of pegylation, which may be applied to liphagal and its analogs to improve aqueous solubility, improve plasma half-life, improve stability, improve biological distribution and/or reduce toxicity.
  • pegylation taught by Zhu et al. wortmannin and 17-hydroxywortmannin which are structurally somewhat similar.
  • the functional groups conjugated to the meroterpenoids may be a biological delivery and targeting molecule.
  • biological delivery and targeting molecules are those that bind to a specific biological substance or site.
  • the biological substance or site is the intended target of the biorecognition molecule that binds to it, enabling the delivery of the meroterpenoid to the tissue or cells of interest.
  • Targeting of the meroterpenoid in this invention is accomplished by conjugating it to a biological delivery and targeting molecule as facilitated by the structural modifications to 17C. Examples of biological delivery and targeting molecules are described below.
  • a ligand may function as a biological delivery and targeting molecule by selectively binding or having a specific affinity for another substance.
  • a ligand is recognized and bound by a specific binding body or binding partner, or receptor.
  • ligands suitable for targeting are antigens, haptens, biotin, biotin derivatives, lectins, galactosamine and fucosylamine moieties, receptors, substrates, coenzymes and cofactors among others.
  • a ligand When applied to the present invention, a ligand includes cancer and tumor antigens such as alpha-fetoproteins, prostate specific antigen (PSA) and CEA, cancer markers and oncoproteins, among others.
  • Other substances that can function as ligands for delivery and targeting are certain steroids, prostaglandins, carbohydrates, lipids, certain proteins or protein fragments (i.e. hormones, toxins), and synthetic or natural polypeptides with cell affinity.
  • Ligands also include various substances with selective affinity for ligators that are produced through recombinant DNA, genetic and molecular engineering.
  • Another type of delivery and targeting molecule is an antibody, which is defined to include all classes of antibodies, monoclonal antibodies, chimeric antibodies, Fab fractions, fragments and derivatives thereof.
  • Other delivery and targeting molecules include enzymes, especially cell surface enzymes such as neuraminidases, plasma proteins, avidins, streptavidins, chalones, cavitands, thyroglobulin, intrinsic factor, globulins, chelators, surfactants, organometallic substances, staphylococcal protein A, protein G, cytochromes, lectins, certain resins, and organic polymers.
  • Preferred delivery and targeting molecules also include various substances such as any proteins, protein fragments or polypeptides with affinity for the surface of any cells or tissues to be targeted by the meroterpenoid. These proteins may be produced through recombinant DNA, genetic and molecular engineering techniques know in the art. Of particular use would be any suitable membrane transfer proteins to facilitate the transfer of the meroterpenoid to the target cell interior.
  • Delivery and targeting molecules are not only desired for delivery to target cell or tissue but also to facilitate the transport of the meroterpenoid into the cell interior.
  • U.S. Pat. No 6,204,054 describes the use of transcytosis vehicles and enhancers capable of transporting physiologically-active agents across epithelia, endothelia and mesothelia containing the GP60 receptor.
  • the GP60 receptor has been implicated in receptor-mediated transcytosis of albumin across cell barriers.
  • U.S. Pat. No 6,204,054 exploits GP60 receptor-mediated transcytosis for the transport of physiologically- active agents which do not naturally pass through epithelia, endothelia and mesothelia via the GP60 system.
  • a meroterpenoid may be coupled to albumin, albumin fragments, anti-GP60 polyclonal and monoclonal antibodies, anti-GP60 polyclonal and monoclonal antibody fragments, and GP60 peptide fragments to facilitate transport into the cell.
  • the conjugation to a functional group may also improve other properties of the meroterpenoid.
  • Such functional groups are often termed drug carriers and can improve the stability, solubility or biocompatibility of the drug being carried.
  • the solubility of the meroterpenoid may be improved by conjugating the meroterpenoid to a peptide polymer.
  • U.S. Pat. Publication No. 2001041189 describes the use of polypeptides (containing glutamic acid and aspartic acid, or glutamic acid/alanine, or glutamic acid/asparagine, or glutamic acid/glutamine, or glutamic acid/glycine) as conjugated to drugs to act as carriers to improve the solubility of the drugs and/or their therapeutic efficacy in vivo.
  • polypeptides containing glutamic acid and aspartic acid, or glutamic acid/alanine, or glutamic acid/asparagine, or glutamic acid/glutamine, or glutamic acid/glycine
  • One such drug exemplified in US 2001041189 is the poorly soluble paclitaxel.
  • 4,675,381 describes a polyaspartate and/or polyglutamate polymer as a drug carrier.
  • This patent suggests the use of polyaspartate and/or polyglutamate polymers as drug carriers wherein the drag is encapsulated or incorporated in the matrix of the polymer.
  • U.S. Pat. No. 5,087,616 describes the use of a biodegradable polymeric carrier to which one or more cytotoxic molecules, such as daunomycin is conjugated.
  • the biodegradable polymeric carrier is specified to be, for example, a homopolymer of polyglutamic acid.
  • U.S. Pat. No. 4,960,790 describes the anti-tumor agent taxol covalently conjugated to an amino acid (glutamic acid).
  • U.S. Pat. No. 5,420,105 describes the use of polypeptide carriers that are capable of binding one drug or multiple drugs.
  • the polypeptide carrier can be further attached to a targeting or delivery protein, such as an antibody or ligand capable of binding to a desired target site in vivo.
  • cyclodextrin polymers are used for carrying drugs and other active agents for therapeutic, medical or other uses.
  • the 2001034333 invention also discloses methods for preparing compositions of cyclodextrin polymer carriers that are further coupled to delivery and targeting molecules for delivery of drugs, like paclitaxel and doxorubicin, to their site of action.
  • U.S. Pat. No. 6,127,349 describes the use of phospholipids to improve the solubility of the therapeutic agents(steroids, peptides, antibiotics and other biologically active agents and pharmaceutical formulations) and to improve their bio-availability.
  • fatty acids could be conjugated to the meroterpenoid in order to stabilize the activity of the anti- angiogenic substances.
  • U.S. Pat. No. 6,380,253 describes the conjugation of anti- angiogenic substances (proteins - angiostatin and endostatin etc.) to cis unsaturated fatty acids or polyunsaturated fatty acids to potentiate and stabilize the activity of the anti- angiogenic substances.
  • PEG Polyethylene glycol
  • Other suitable drug carriers include Polyethylene glycol (PEG) and related polymer derivatives.
  • PEG Polyethylene glycol
  • Such drug-PEG conjugates have been described as improving the circulation time (prolong serum half-life) before hydrolytic breakdown of the conjugate and subsequent release of the bound molecule thus increasing the drugs efficacy.
  • U.S. Pat. No. 6,214,966 describes the use of PEG and related polymer derivatives having weak, hydrolytically unstable linkages near the reactive end of the polymer to conjugate to drugs such as proteins, enzymes and small molecules.
  • EP 1082105 (WO9959548) describes the use of biodegradable polyester polymers as a drug delivery system to facilitate controlled release of the conjugated drug.
  • the compounds described herein may be conjugated to a Cremophor such as, Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative, to improve the solubilization of drugs
  • the meroterpenoid may be conjugated to another pharmaceutically active compound to enhance the therapeutic effect on the target cell or tissue by delivering a second compound with a similar anti-mitotic effect or a different activity altogether.
  • US 6,051,576 describes the use of codrug formulations by conjugating two or more agents via a labile linkage to improve the pharmaceutical and pharmacological properties of pharmacologically active compounds.
  • Racemic mixtures of Liphagal and its analogs may be useful for inhibition of PD kinases.
  • the stereo-isomer of Liphagal having the absolute configuration 5R, 8R and HS as shown in compound (1).
  • any compound of this invention having a chiral center will be an enantiomer having a configuration at the chiral center(s) that is the same as the configuration at a corresponding chiral center in the enantiomer of liphagal having the configuration 5R, 8R, US.
  • TABLE 3 shows compounds to be specifically excluded from the novel compounds claimed herein.
  • TABLE 4 shows specific compounds excluded when the generic formulas do not allow for carbon substitutions within the rings other than the oxygen at position 10.
  • the compounds of the present invention exhibit PDK inhibitory activity and may therefore be useful to inhibit abnormal cell growth in which PI3K plays a role.
  • Such compounds may be effective in the treatment of disorders with abnormal cell growth such as, but not limited to, restenosis, atherosclerosis, arthritis, diabetic retinopathy, psoriasis, benign prosthetic hypertrophy, pancreatitis and cancers.
  • the compounds described herein may be useful to inhibit cancer cell growth and metastasis, particularly in solid cancers and malignant lymphomas, and especially, for example, in leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovarian cancer, colorectal cancer, pancreatic cancer, renal cancer, gastric cancer and brain cancer.
  • the compounds described in the present application would be suitable for administration in combination therapies with a traditional chemotherapeutic agent or radiotherapy, or in combination with another PB K inhibitor etc.
  • the 1 H and 13 C NMR spectra were recorded on a Braker AMX-500 and AM400 spectrometers, respectively.
  • 1 H chemical shifts are referenced to the residual DMSO-d 6 signal ( ⁇ 2.49 ppm) and 13 C chemical shifts are referenced to the DMSO-d 6 solvent peak ( ⁇ 439.5 ppm).
  • Low and high resolution mass spectra were recorded on Kratos AEI MS-59 and AEI MS-50 mass spectrometers.
  • UV spectra were recorded with a Waters 2487 Dual ⁇ Absorbance Detector.
  • Optical rotations were measured using a Jasco P- 1010 Polarimeter with sodium light (589 nm).
  • Liphagal (1) was obtained as an optically active ([ ⁇ ]25 ⁇ j +12.0° (c 3.7, MeOH)) amorphous yellow solid that gave a [M] + ion in the HREIMS at ni/z 356.1994 appropriate for a molecular formula of C 22 H 28 O 4 (calcd 356.1988), requiring nine sites of unsaturation.
  • the 13 C NMR spectrum (Supporting Information) obtained for 1 contained resonances that could be assigned to 22 carbon atoms consistent with the HRMS data.
  • HMQC data showed that only 26 of the hydrogen atoms were attached to carbon (4 x CH3, 5 x CH2, 4 x CH, 9 x C), requiring the presence of 2 OHs. Broad singlets at ⁇ 9.29 and 10.28 in the 1 H NMR spectrum, that were not correlated to carbon resonances in the HMQC spectrum, were assigned to the OH protons.
  • Structural features of 1 identified from the NMR data were similar to the structural components of siphonodictyal B (5) (Sullivan, B. W.; Faulkner, J. J. Org. Chem. 1986, 51, 4568-4573; and Sullivan, B.; Djura, P.; Mchityre, D.; Faulkner, DJ. Tetrahedron 1981, 37, 979-982), previously isolated from specimens of A. coralliphaga collected in Caribbean, suggesting that the compounds were related.
  • COSY correlations identified the spin system extending from the methylene protons at C-I ( ⁇ 1.38 and 2.47) through to the methylene protons at C-3 ( ⁇ 1.21 and 1.43), and starting from H-5 ( ⁇ 1.50) through to H-8 ( ⁇ 3.16) and Me-21 ( ⁇ 1.36).
  • the H-8 ( ⁇ 3.16) and Me-22 (1.28) resonances showed HMBC correlations to the C-10 ( ⁇ 124.4) resonance, and the H-7 ⁇ ( ⁇ 2.12), H-8 (3.16), and Me-21 (1.36) resonances showed correlations to the C-9 ( ⁇ 155.2) resonance, demonstrating the presence of a seven membered ring B with a tetrasubstituted ⁇ (Sullivan (1986) supra; Sullivan (1981) supra; Inoue, M.; Carson, M. W.; Frontier, AJ.; Danishefsky, SJ. /. Am. Chem. Soc. (2001) 123, 1878-1889) olefin.
  • Liphagal (1) which represents the first example of the 'liphagane' meroterpenoid carbon skeleton, and frondosins A to E (i.e. B (6)) isolated from Dysidea frondosa (Patil AD.
  • Siphonodictyal (5) could be converted to liphagal (1) via the epoxide VII followed by ring expansion to ketone VIII, epimerization at C-8 and hemiketal formation to give IX, and dehydration, hi pathway B, it is the 2' carbon of the prenyl residue that acts as a nucleophilic center in the polyene cyclization step.
  • Pathway A outlines an alternate and more direct biogenetic route to liphagal (1). This proposal suggests that a farnesylated trihydroxybenzaldehyde I is converted to the ketone
  • the corallidictyals 7 can be formed by trapping the transient C-7' carbocation formed in V with the alternate nucleophilic site C-2' of the benzofuran moiety. Proton initiated ring expansion of the corallidictyals (7) could lead directly to liphagal (1).
  • the corallidictyals 7 might alternatively be formed from the pathway A orthoquinone intermediate X via the C-8 epimer XI.
  • synthesis examples provided herein are merely representative of synthesis methods used to produce liphagal and des formyl liphigal and are not intended to be limiting in any way.
  • a person of skill in the art would know to make changes to the starting components to produce analogs of liphagal.
  • the Br in compound 9 of Scheme 2 below may be removed to produce deformyl liphagal as set out in the deformyl liphagal synthesis below.
  • Using the basic sythesis schemes below a person of skill in the art would be able to make analogs of liphagal, through simple modifications.
  • racemic liphagal (1) started with preparation of the desired cyclization precursor 17 (Scheme 2).
  • Commercially available 2,4,5-trimethoxybenzaldehyde 8 was selectively demethylated at the 2 position with BBr 3 and the resulting phenol was brominated at C-3 to give 9.
  • Direct reduction of the aldehyde 9 led to an unstable diol (Kraus, G.A.; Nguyen, T.; Bae, J.; Hostetter, J.; Steadham, E. Tetrahedron 2004, 60, 4223-4225.), so it was necessary to use a protection sequence to get the desired phosphonium salt 11.
  • the key cyclization step was first effected by refluxing 17 in a biphasic system of formic acid and cyclohexane (Scheme 3) (Hercouet A. Le Corre, M. Tetrahedron Lett. 1979, 23, 2145) for 14 days to give a racemic mixture 19 of C-8 epimers as a minor product accompanying a mixture of inseparable partially cyclized alkenes 18, suggesting that the conversion of 17 to 19 proceeded in two steps.
  • Scheme 3 formic acid and cyclohexane
  • the aldehyde functionality was introduced by treatment of the isomeric mixture of bromobenzenes 19 with n-butyllithium to give the corresponding phenyllithium mixture that was condensed with DMF followed by hydrolysis.
  • the resulting aldehydes 20a and 20b were separated by normal phase HPLC to give the desired product 20a, which had the trans 6,7 ring junction and the Me-21 alpha configuration as determined by 1 D NOESY analysis.
  • Compound 20b obtained from the HPLC purification crystallized and x-ray diffraction analysis confirmed that it had the Me-21 beta configuration (Supporting
  • EXAMPLE 6 PBK FLUORESCENCE POLARIZATION ASSAY Natural product extracts were tested for PDkinase inhibitors by employing a fluorescent polarization assay using purified human PDK alpha and gamma (as GST-fusions and FLAG tagged) were expressed in SF9 insect cells and purified by GSH-Sepharose and FLAG affinity columns. Mouse GST-GRPl was expressed in E. coli and purified by GSH-Sepharose.
  • Fluorescence polarization is based on Echelon Bioscience assay kit K- 1100, a competitive FP assay where PIP3 produced in the enzyme reaction competes with a fluorescent-labelled PIP3 analog bound to GRP protein.
  • Reaction Buffer 2OmM Hepes pH7.5, 2mM MgC12, 0.05% CHAPS, and 0.01% bME (added fresh)
  • STOP/detection Buffer 10OmM Hepes pH7.5, 4mM EDTA, 0.05% CHAPS
  • STOCKS ATP 2OmM in H2O
  • GST-murineGRP 1.5mg/ml in 17% glycerol
  • Plate Nunc 384 well black polypropylene fluorescence plates.
  • the assay is run by putting 9.5ul of freshly diluted enzyme (in "reaction buffer") per well, then 0.5ul of diluted drug or DMSO mixing. Then lOul of substrate to start the reaction. Incubated 30-60 minutes, room temp, then stopped with 20ul of stop/detector mix. Substrate solution, 40 uM PIP2, 5OuM ATP in reaction buffer. lOul of substrate is then added to each well to start reaction. There is 2OuM PIP2, 25uM ATP final in reaction.
  • Stop/detector mix 1OnM TAMRA detector, 4OnM GST-GRP in STOP/detection buffer
  • the reaction is stopped by adding 20ul Stop/detector mix per well and mix well. After 90- 110 minutes the plates may be read. Plates are read on Perkin-Elmer Envision plate readers with filters for Tamra. This procedure is adapted from Echelon Biosciences Inc procedure for their PI3-Kinase fluorescence polarization activity Assay kit Product number K-1100.
  • Cells were plated at about 2000 cells per well in 96 well plates. Cells are plated in media (200 ⁇ l) and allowed to adhere overnight at 37°C. At 24 hours post plating, compounds were added directly at a volume of 0.5 ⁇ l in DMSO. The cells are then incubated for four days after which the media is removed, 200 ⁇ l of DPBS is then added to each well, followed by the careful addition of 500 ⁇ l of 50% TCA. The plates were then incubated for greater than 1 hour at 4°C, after which the plates were washed 4 to 6 times with greater than 200 ⁇ l of water.
  • the plates were then air dried and 100 ⁇ l of sulforhodamine B (SRB) stock solution (0.4% (w/v) in 1% acetic acid) is added.
  • SRB sulforhodamine B
  • the SRB is incubated with fixed cells for at least 15 minutes at room temperature after which the SRB is removed and the plates washed 3 to 4 times with 350 ⁇ l of 1% acetic acid per well.
  • the plates are then air dried after which the bound SRB is released from protein by the addition of 200 ⁇ l of Tris base followed by shaking for 15 to 30 minutes.
  • the absorbance of each well is determined at 570 nm using a microtiter plate reader.
  • liphagal (1) was cytotoxic to LoVo (human colon: IC 50 0.58 ⁇ M), CaCo (human colon: IC 50 0.67 ⁇ M), and MDA-468 (human breast: IC 50 1.58 ⁇ M) tumor cell lines.
  • IC 50 S were determined at various concentrations of ATP (below and above the Km of the enzyme for ATP) and the equation was used to determine what the ratio of the IC50s should be. Without any equation, it would be expected that the IC 50 would go up dramatically with a 10-fold increase of ATP if the cpd competes with ATP (as is seen for the LY294002 cpd).
  • the general protocol is described in Cheng Y-C. and Prusoff WH. (1973) Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzymatic reaction. Biochemical Pharmacology 22:3099-3108.
  • SUMMARY Liphagal (1) is a PI3K inhibitory meroterpenoid with the new 'liphagane' carbon skeleton, which has been isolated from the Caribbean marine sponge Aka coralliphaga.
  • the key step in the achiral biomimetic synthesis of 1 is the first example of the formation of a seven membered ring by trapping a carbocation with a benzofuran.
  • Liphagal (1) is a more potent inhibitor of PDK alpha than LY294002 (3) and more selective than wortmannin (2). It shows significant in vitro cytotoxicity against a small panel of human tumor cell lines.
  • the potency and selectivity of liphagal for the PI3K alpha isoform and its in vitro cytotoxicity against human tumor cell lines make it a promising lead structure for the development of a new class of PI3K inhibitors.

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Abstract

L'invention concerne des compositions avec un squelette carboné méroterpénoïde à liphagane unique (structures I, II, III) ainsi que des compositions pharmaceutiques et leur utilisation. Il y est décrit un procédé d'inhibition de l'activité de la phosphoinositide 3 kinase (PI3K). En particulier, l'invention décrit un procédé d'inhibition de la PI3 K, où le composé est un liphagal, desformyl liphagal, desméthyl liphagal ou déshydroxy-desformyl liphagal. Les procédés et les utilisations en question sont destinés au traitement de maladies proliférantes, en particulier celles dans lesquelles la P13K alpha est impliquée.
PCT/CA2006/000131 2005-02-01 2006-02-01 Inhibiteurs meroterpenoides de la phosphoinositide 3 kinase (pi3k) Ceased WO2006081659A1 (fr)

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WO2012166987A3 (fr) * 2011-05-31 2013-04-11 California Institute Technology Enantiomères de liphagal et leurs dérivés et précurseurs, et procédés énantiosélectifs de fabrication de ceux-ci
EP2685821A4 (fr) * 2011-03-15 2014-08-20 Abbvie Inc Modulateurs des récepteurs hormonaux nucléaires
CN104395325A (zh) * 2012-03-19 2015-03-04 科学与工业研究委员会 带有硼酸的LIPHAGANE化合物作为PI3K-α和/或β的抑制剂
US9150592B2 (en) 2012-12-21 2015-10-06 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
US9193744B2 (en) 2012-09-07 2015-11-24 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
WO2018203564A1 (fr) 2017-05-02 2018-11-08 国立大学法人東北大学 Analogue de liphagal et inhibiteur de kinase multi-cible contenant du liphagal ou un analogue de celui-ci
CN109715638A (zh) * 2016-09-16 2019-05-03 巴斯夫欧洲公司 制备作为类胡萝卜素的结构单元的鏻盐酯的方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2685821A4 (fr) * 2011-03-15 2014-08-20 Abbvie Inc Modulateurs des récepteurs hormonaux nucléaires
WO2012166987A3 (fr) * 2011-05-31 2013-04-11 California Institute Technology Enantiomères de liphagal et leurs dérivés et précurseurs, et procédés énantiosélectifs de fabrication de ceux-ci
US8653307B2 (en) 2011-05-31 2014-02-18 California Institute Of Technology Liphagal enantiomers and their derivatives and precursors, and enantioselective methods of making the same
CN104395325A (zh) * 2012-03-19 2015-03-04 科学与工业研究委员会 带有硼酸的LIPHAGANE化合物作为PI3K-α和/或β的抑制剂
TWI577687B (zh) * 2012-03-19 2017-04-11 印度科學與工業研究理事會 作為ＰＩ３Ｋ－α及／或β抑制劑之帶有硼酸之立費烷（ＬＩＰＨＡＧＡＮＥ）化合物
US9193744B2 (en) 2012-09-07 2015-11-24 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
US9150592B2 (en) 2012-12-21 2015-10-06 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
CN109715638A (zh) * 2016-09-16 2019-05-03 巴斯夫欧洲公司 制备作为类胡萝卜素的结构单元的鏻盐酯的方法
WO2018203564A1 (fr) 2017-05-02 2018-11-08 国立大学法人東北大学 Analogue de liphagal et inhibiteur de kinase multi-cible contenant du liphagal ou un analogue de celui-ci
JPWO2018203564A1 (ja) * 2017-05-02 2020-03-12 国立大学法人東北大学 リファガールの類縁体、及びリファガール又はその類縁体を含む多標的キナーゼ阻害剤
JP7260912B2 (ja) 2017-05-02 2023-04-19 国立大学法人東北大学 リファガールの類縁体、及びリファガール又はその類縁体を含む多標的キナーゼ阻害剤
US11691980B2 (en) 2017-05-02 2023-07-04 Tohoku University Liphagal analog and multi-targeted kinase inhibitor containing liphagal or analog thereof

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