WO2021150697A1 - Dérivés de 3-tricyclyl-pipéridines n-substituées utilisés en tant qu'agents anticancéreux et neuroprotecteurs - Google Patents

Dérivés de 3-tricyclyl-pipéridines n-substituées utilisés en tant qu'agents anticancéreux et neuroprotecteurs Download PDF

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WO2021150697A1
WO2021150697A1 PCT/US2021/014342 US2021014342W WO2021150697A1 WO 2021150697 A1 WO2021150697 A1 WO 2021150697A1 US 2021014342 W US2021014342 W US 2021014342W WO 2021150697 A1 WO2021150697 A1 WO 2021150697A1
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compound according
disease
hydrogen
patient
cancer
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Michael Ohlmeyer
Nilesh ZAWARE
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Icahn School Of Medicine At Mount Sinai
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

Definitions

  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • a sterile liquid carrier for example saline, phosphate-buffered saline (PBS) or the like.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the compounds provided herein can be used for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • the cancer is characterized by dysregulation of the PI3K-AKT-FOXO signaling pathway.
  • the cancer can be selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
  • the method further comprises administering one or more additional cancer chemotherapeutic agents.
  • the one or more additional cancer chemotherapeutic agents are EGFR inhibitors.
  • Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue.
  • Allo-HCT allogeneic hematopoietic cell transplants
  • compounds of the present invention are useful in treatment of autoimmune and related diseases, by activating FOXO proteins and inducing T cell differentiation to Tregs.
  • Compounds may be administered therapeutically to subjects directly, or alternatively, T cells may be collected from a subject and differentiated ex vivo to Tregs as described by Taylor et al. [Blood 99, 3493-3499 (2002)].
  • aspects of the invention include methods for treatment of autoimmune disease characterized by deficiency in Treg function comprising administering a therapeutically useful amount of compound of formula I.
  • the method can also include extraction of naive T-cells from a patient, differentiation of T-cells to Tregs ex vivo by treatment with a compound of formula I, optionally supplemented with an HDACi, followed by administration of Tregs to patient with optional separation of compound of formula I from Tregs prior to their administration.
  • autoimmune diseases that can be so treated include IBD, solid organ transplant rejection, and GvHD in allo-HCT.
  • the compounds can be administered to a patient to treat an autoimmune disorder, for example, Addison’s disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barre syndrome (GBS), Graves’ disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis.
  • an autoimmune disorder for example, Addison’s disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barre syndrome (GBS), Graves’ disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis.
  • the compound provided herein can be used for treating a disease or disorder in a patient wherein the disease or disorder involves excessive or unregulated cellular proliferation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • a method for treating a disease in a patient wherein the disease is characterized by proteotoxicity, including age onset proteotoxicity leading to neurodegeneration comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • Hyperphosphorylated Tau has been implicated as the pathogenic protein in several neurodegenerative diseases and furthermore PP2A has been shown to be an important phosphatase in reversing aberrant phosphorylation of Tau; see for example Ludovic Martin et al., Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A in Ageing Research Reviews 12 (2013) 39- 49; Miguel Medina and Jesus Avila, Further understanding of tau phosphorylation: implications for therapy in Expert Rev.
  • Hyperphosphorylated alpha- Synuclein is a second exemplar of a toxic protein, and again PP2A has been shown to reverse its aberrantly phosphorylated state; see for example Kang-Woo Lee et al., Enhanced Phosphatase Activity Attenuates alpha-Synucleinopathy in a Mouse Model in Neurobiology of Disease, May 11, 2011, 31(19) 6963-6971.
  • the compounds provided herein may further be used in a method for treating a mood disorder in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • the mood disorder is stress- induced depression.
  • Protein phosphatase 2A is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and COPD.
  • PP2A has shown to be dysregulated in mouse models of COPD, and inhibiting PP2A activity exacerbated inflammatory responses in the lung.
  • CSE cigarette smoke extract
  • increasing PP2A activity by treatment with compounds of the present invention may ameliorate or reverse the pathology underlying lung diseases such as COPD.
  • the cardiac hypertrophy is associated with a disease selected from hypertension, myocardial infarction, heart failure, and valvular heart disease.
  • Cardiac physiology and hypertrophy are regulated by the phosphorylation status of many proteins, including receptors and ion channels, which is partly controlled by a PP2A-alpha4 intracellular signalling axis. Studies indicate that the type 2A protein phosphatases are differentially regulated in both the healthy and hypertrophied myocardium.
  • treatment with compounds of the present invention may ameliorate cardiac hypertrophy.
  • significant reduction in endosomal PP2A activity has been observed in heart failure samples versus controls, suggesting that inhibited resensitization of beta-adrenergic receptors occurs in human heart failure.
  • These studies suggest that resensitization of beta adrenergic receptors is inhibited in human heart failure and targeting the PP2A inhibitor SET to derepress and activate PP2A may provide preservation of receptor function and beneficial cardiac remodeling.
  • treatment with compounds of the present invention may have a beneficial effect in heart failure.
  • a method for treating a parasitic infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • parasites that may cause parasitic infections to be treated include, but are not limited to, Plasmodium and Theileria.
  • a method for treating inflammatory conditions is provided herein.
  • Reduced PP2A activity occurs in animal models of allergic airway disease and patients with severe asthma.
  • Treatment with small molecule activators of PP2A such as fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-l-ol (AAL(S)) inhibited the development of inflammation, airway hyperreactivity in mouse models of allergic airway disease.
  • FTY720 fingolimod
  • AAL(S) 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-l-ol
  • compounds of the present invention may be useful in the treatment of asthma.
  • Dephosphorylation of tristetraprolin (TTP) functions as an “off-switch” in inflammatory responses, and can be promoted by compounds that stimulate PP2A activity.
  • PP2A enzymes are involved in the regulation of cell transcription, cell cycle, and viral transformation.
  • Many viruses including cytomegalovirus, parainfluenza, DNA tumor viruses, and HIV-1, utilize different approaches to exploit PPA2 in order to modify, control, or inactivate cellular activities of the host [Garcia et al., Microbes and Infection, 2, 2000, 401-407] Therefore, the compounds provided herein may further be used in a method for treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • Serine/Threonine phosphatases are involved in modulation of synaptic plasticity (D. G. Winder and J. D. Sweatt, Nature Reviews Neuroscience, vol 2,
  • PP2A activators described here may be useful as treatments for psychostimulant abuse.
  • Mammalian target of rapamycin is a serine/threonineprotein kinase that regulates cell growth, proliferation, and survival: mTOR is frequently activated in human cancers and is a commonly sought anticancer therapeutic target.
  • PP2A is a key element in mTOR-AKT signaling during nutritional deprivation, and it has important implications in cell cycle progression and quiescence. Dysregulation of cellular metabolism is a feature of cancer, with nutrient transport defects, nutrient sensing defects, dysregulated autophagy and constitutive anabolism being common in tumors; aberrant activation of mTOR is implicated in all of these processes and PP2A activation has been demonstrated to modulate them in vivo.
  • PP2A has been shown to be involved in regulatory feedback loops with mTOR, and PP2A activators of the present invention would be expected to affect these processes directly by interacting with mTOR complexes, or indirectly by counterbalancing mTOR’s effects by dephosphorylating its targets.
  • Perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders, and neurodegenerative conditions such as Alzhiemer’s disease.
  • Activation of PP2A has been shown to be effective in animal models of neurodegenerative disease by modulating the PP2A mTOR axis; thus, molecules of the present invention will be useful in treatment of these conditions.
  • PP2A activators of the present invention are likely to be useful in the treatment of diseases in which mTOR signaling is dysregulated; these include cancer, diabetes and neurodegenerative conditions.
  • Compounds of the present invention may also promote innate immunity to infection and promote healthy aging.
  • a method or composition that “comprises”, “has”, “includes” or “contains” one or more steps or elements possesses those one or more steps or elements, but is not limited to possessing only those one or more steps or elements.
  • a step of a method or an element of a composition that “comprises”, “has”, “includes” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features.
  • the terms “comprising” and “including” or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof.
  • "X includes a, b and c” means that X includes, but is not limited to, a, b and c. This term encompasses the terms “consisting of’ and “consisting essentially of’.
  • X can be a halogen, such as fluorine or chlorine
  • X can be, but is not limited to, fluorine or chlorine.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succin
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
  • subject or “subject in need thereof or “patient” are used interchangeably herein. These terms refer to a patient who has been diagnosed with the underlying disorder to be treated. The subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. Additionally, a "subject in need thereof may be a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made. As anon-limiting example, a "subject in need thereof, for purposes of this application, may include a male who is currently diagnosed with prostate cancer or was diagnosed with prostate cancer in the past, regardless of current symptomatology.
  • a “patient,” as used herein, includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, for example, a primate.
  • the patient is a human.
  • treatment or “treating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit.
  • Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated; it also includes the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • Treatment can involve administering a compound described herein to a patient diagnosed with a disease, and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • administer refers to the act of introducing the dosage form into the system of subject in need of treatment.
  • administration and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents.
  • Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration.
  • the therapies are administered at approximately the same time, e.g. , within about a few seconds to a few hours of one another.
  • a “therapeutically effective” amount of the compounds described herein is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. A therapeutic benefit is achieved with the amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the term “modulate” with respect to a FOXO transcription factor protein refers to activation of the FOXO transcription factor protein and its biological activities associated with the FOXO pathway. Modulation of FOXO transcription factor proteins includes up- regulation (i.e., agonizing, activation or stimulation).
  • the mode of action of a FOXO modulator can be direct, e.g., through binding to the FOXO transcription factor protein as a ligand. The modulation can also be indirect, e.g., through binding to and/or modifying another molecule which otherwise binds to and activates the FOXO transcription factor protein.
  • Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbomyl, etc.
  • Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
  • alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof.
  • Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
  • Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy -propyl, cy-butyl, cy- pentyl, norbomyl and the like.
  • Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methyl enedioxy and ethylenedioxy.
  • halogen means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
  • haloalkyl means alkyl, alkoxy, or alkylthio, respectively, substituted with one or more halogen atoms.
  • Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized.
  • a heterocycle may be non-aromatic (heteroaliphatic) or aromatic (heteroaryl).
  • heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and tetrahydroquinolinyl.
  • heteroaryls examples include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • examples of heteroaryls include imidazole, pyridine, thiophene, thiazole, furan, pyrimidine, pyrazine, tetrazole and pyrazole.
  • the term “optionally substituted” may be used interchangeably with “unsubstituted or substituted”.
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • Oxo may also be included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
  • 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
  • more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene and P.G.M.Wuts [John Wiley & Sons, New York, 1999], in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; and in March ’s Advanced Organic chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley-Interscience Publication, 2001.
  • the unsaturated intermediate may reacted to give ureas, sulfonyl ureas, or their bioisosteres to give compounds of formula I.
  • the ring double bond may then be optionally derivatized by, for example, hydrogenation, dihydroxylation or cyclopropanation. Alternatively the ring double bond may be derivatized, followed by N-deprotection and urea (or isostere) formation. These are shown schematically in SCHEME B. SCHEME B. Synthesis of Compounds of Formula I
  • a 175 mL chem. glass ® pressure vessel was charged with Pd 2 .dba 3 . CHCl 3 (0.621 g, 0.600 mmol), and triphenylphosphine (0.472 g, 1.80 mmol). The vessel was sealed, evacuated and backfilled with argon three times. Dry degassed dichloromethane (33.0 mL) was added, and the mixture was stirred at room temperature for 60 min.
  • Racemic tert-butyl 5-(( tert-butoxycarbonyl)oxy)-5.6-dihydropyridine- l(2H)-carboxylate (8.62 g, 28.8 mmol) was added followed by 10H-phenoxazine (2.19 g, 12.0 mmol) in dry degassed dichloromethane (28.0 mL). The reaction mixture was sealed and stirred at room temperature for 10 days.
  • reaction mixture was evaporated onto silica gel and subjected to column chromatography (S1O 2 ; 0%-5% ethylacetate in hexanes) to afford crude tert-butyl 5-( 10H-phenoxazin- 10-yl)-5.6-dihydropyridine- 1 (2H)-carboxylate (4.09 g) that was taken to the next step without purification.
  • Residue was purified by column chromatography (S1O 2 , 17% acetone in hexanes) to afford N-(4- chlorophenyl)-3-(10H-phenoxazin-10-yl)piperi dine- 1 -carboxamide (0.015 g, 16%).
  • Residue was purified by semi-prep HPLC (XDB-C18, 9.4 mm x 250 mm, 18 injections of 200 microliters, 4 mL/min, 12 min, 90% ACN: Water (Isocratic)) to afford 3-(10H-phenoxazin-10-yl)-N-(4-(trifluoromethoxy)phenyl)piperidine-l- carboxamide (0.020 g, 25%).
  • the salt was suspended in toluene (3.6 mL) and PCb (0.745 g, 3.58 mmol) was added. The mixture was stirred at 75 °C for 3 h, cooled to RT and filtered. Solid residue was washed with toluene and filtrate was collected. The filtrate was evaporated and dried under high vacuum. The crude phenylsulfamoyl chloride (0.635 g) was used for the next step without further purification.
  • the salt was suspended in toluene (6.0 mL) and PCb (0.782 g, 3.76 mmol) was added. The mixture was stirred at 75 °C for 3 h, cooled to RT, and filtered. Solid residue was washed with toluene and filtrate was collected. The filtrate was evaporated and dried under high vacuum. The crude (4-(trifluoromethoxy)phenyl)sulfamoyl chloride (1.01 g) was used for the next step without further purification.
  • N-(4-chlorophenyl)-3-(10H-phenoxazin-10-yl)piperidine-1-sulfonamide (Ex. 4): To a solution of 4chloroaniline (1.44 g, 11.3 mmol) in DCM (12 mL), placed in ice bath under argon, was added a solution of chlorsulfonic acid (0.438 g, 3.76 mmol) in DCM (2.0 mL). The reaction mixture was stirred at 0 °C for 30 min, and at RT for 1 h. Precipitate was collected by filtration and dried under high vacuum.
  • the salt was suspended in toluene (6.0 mL) and PCl 5 (0.782 g, 3.76 mmol) was added. The mixture was stirred at 75 °C for 3 h, cooled to RT, and filtered. Solid residue was washed with toluene and filtrate was collected. The filtrate was evaporated and dried under high vacuum. The crude (4- chlorophenyl)sulfamoyl chloride (0.840 g) was used for the next step without further purification.
  • the activated pyrrolidine derivative is used as an alkylating agent for optionally substituted tricyclics such as carbazoles, phenoxazines, dibenzazepines or phenothiazines (or their heterocyclic analogs). Displacement of the leaving group is carried out in the presence of a base to deprotonate the tricyclic in an aprotic solvent with optional heating.
  • tricyclics such as carbazoles, phenoxazines, dibenzazepines or phenothiazines (or their heterocyclic analogs).
  • N-Boc-2,5- dihydropyrrole may be dihydroxylated and activated as a cyclic sulfite or cyclic sulfate which is then ring opened by nucleophilic displacement with a tricyclic in an analogous manner to the epoxide.
  • the hydroxy intermediate is N-Boc deprotected and reacted with an optionally substituted aryl sulfamoyl chloride to give the requisite sulfonyl urea, or with an optionally substituted aryl isocyanate to give the urea.
  • the double bond of Intermediate 1 may be hydrogenated under mild conditions, for example by stirring under hydrogen atmosphere with 10% palladium on charcoal in methanol, filtration through celite and concentration.
  • the hydrogenated material is boc-deprotected by treatment with acid such as trifluoroacetic acid in methylene chroride or HC1 in dioxane.
  • the deprotection reaction is concentrated, dissolved in ethyl acetate and washed with 1M sodium hydroxide, saturated brine and dried over anhydrous sodium sulfate.
  • the organic is concentrated and the residue purified by chromatography, to give the piperidine, Intermediate 2.
  • R B is H or (C 1 -C 6 )alkyl;
  • U is selected from
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C 1 -C 7 ,)alkyl optionally substituted with -OH, (C 1 -C 6 )haloalkyl, (C 1 - C 6 )haloalkoxy, (C 1 -C 6 )haloalkylthio, -NR 1 R 2 , -OR 1 , -C(O)R 1 , -OC(O)R 1 , -C(O)NR 1 R 2 , - C(O)OR 1 , -SR 1 , -SO 2 R 1 , and -SO 2 NR 1 R 2 ;
  • R 3 -R 4 is selected from m is zero, 1 or 2; n is 1 or 2; wherein m + n equals 1, 2 or 3; and wherein when m is zero and n is 1, R 3 -R 4 is either
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C 1 -C 6 )alkyl optionally substituted with -OH, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkylthio, -NR 3 R 2 , -OR 1 , - C(O)R 1 , -OC(O)R 1 , -C(O)NR 1 R 2 , -C(O)OR 1 , -SR 1 , -SO 2 R 1 , and -SO 2 NR 1 R 2 .
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, nitro, cyano, azido, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 - C 6 )haloalkoxy, (C 1 -C 6 )haloalkylthio, -NR'R 2 .
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, -NR 1 C(O)OR 6 , and halo(C 1 -C 6 )alkoxy.
  • R B is H or (C 1 -C 6 )alkyl
  • U is selected from and m is 1 and n is 1, or m is 2 and n is 1, or m is 1 and n is 2
  • X 2 and X 4 are each hydrogen, and X 1 and X 3 are each chosen independently from -H, -F, -Cl, -CF 3 ,-C(CH 3 ) 2 OH, - C(O)NMe 2
  • R 1 and R 2 are independently selected in each instance from the group consisting of hydrogen and (C 1 -C 6 )alkyl
  • V is phenyl
  • Z 1 is hydrogen
  • Z 2 is selected in each instance from hydrogen, halogen, and (C 1 -C 6 )haloalkoxy.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of [1] to [88] above, or according to other embodiments of the invention.
  • (k) inflammatory conditions such as asthma
  • the method comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [88] above, or according to other embodiments of the invention.
  • (k) inflammatory conditions such as asthma; the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [89] above, or according to other embodiments of the invention.
  • cancer selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
  • a virus selected from influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus.
  • a method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer comprising administering an effective amount of a compound of any of [1] to [88] above, or according to other embodiments of the invention.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [88] above, or according to other embodiments of the invention.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [88] above, or according to other embodiments of the invention.
  • a method for treating a metabolic disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis comprising administering to the patient a therapeutically effective amount of a compound of any of [1] to [88] above, or according to other embodiments of the invention.
  • [104] A method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer, the method comprising administering an effective amount of a pharmaceutical composition of [89] above, or according to other embodiments of the invention.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [89] above, or according to other embodiments of the invention.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [89] above, or according to other embodiments of the invention.
  • a method for treating a metabolic disease or disorder in a patient wherein the disease or disorder involves the dysregulation of the mTOR-PP2A signaling axis comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of [89] above, or according to other embodiments of the invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un genre de dérivés de 3-tricyclyl-pipéridines N-substituées. Les composés sont du genre ci-après. Les composés induisent la translocation du facteur de transcription FOXO1 vers le noyau par modulation de PP2A et, en conséquence, présentent des effets anti-prolifératifs. Ils sont utiles dans le traitement de divers troubles, notamment en monothérapie dans le traitement du cancer, ou utilisés en combinaison avec d'autres médicaments pour restaurer la sensibilité à la chimiothérapie lorsqu'une résistance s'est développée.
PCT/US2021/014342 2020-01-22 2021-01-21 Dérivés de 3-tricyclyl-pipéridines n-substituées utilisés en tant qu'agents anticancéreux et neuroprotecteurs WO2021150697A1 (fr)

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Cited By (1)

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WO2023209191A1 (fr) * 2022-04-29 2023-11-02 University Of Helsinki Ligands de liaison de prep

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US20050009814A1 (en) * 2002-02-05 2005-01-13 Ajinomoto Co., Inc. Pharmaceutical composition containing gabapentin or pregabalin and N-type calcium channel antagonist
US20110136790A1 (en) * 2008-07-23 2011-06-09 De Lera Ruiz Manuel Tricyclic Heterocyclic Derivatives and Methods of Use
WO2017044569A1 (fr) * 2015-09-09 2017-03-16 Icahn School Of Medicine At Mount Sinai Sulfonamides hétérocycliques tricycliques contraints en tant qu'agents anti-cancéreux

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US20050009814A1 (en) * 2002-02-05 2005-01-13 Ajinomoto Co., Inc. Pharmaceutical composition containing gabapentin or pregabalin and N-type calcium channel antagonist
US20110136790A1 (en) * 2008-07-23 2011-06-09 De Lera Ruiz Manuel Tricyclic Heterocyclic Derivatives and Methods of Use
WO2017044569A1 (fr) * 2015-09-09 2017-03-16 Icahn School Of Medicine At Mount Sinai Sulfonamides hétérocycliques tricycliques contraints en tant qu'agents anti-cancéreux

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WO2023209191A1 (fr) * 2022-04-29 2023-11-02 University Of Helsinki Ligands de liaison de prep

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