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WO2012088712A1 - Composé en tant qu'inhibiteur de signalisation de wnt, composition et applications - Google Patents

Composé en tant qu'inhibiteur de signalisation de wnt, composition et applications Download PDF

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Publication number
WO2012088712A1
WO2012088712A1 PCT/CN2010/080613 CN2010080613W WO2012088712A1 WO 2012088712 A1 WO2012088712 A1 WO 2012088712A1 CN 2010080613 W CN2010080613 W CN 2010080613W WO 2012088712 A1 WO2012088712 A1 WO 2012088712A1
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Prior art keywords
amine
methylpyridin
methyl
pyridin
pharmaceutical composition
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Songzhu An
Chufang LI
Chen Huang
Guisheng Zhou
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Curegenix Inc
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Curegenix Inc
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    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a compound as inhibitor of WNT signal transduction pathway, as well :as a composition comprising the same. Further, the present invention relates to the use of the compound and the method of inhibiting the WNT signal transduction pathway.
  • WNT signaling is important to both embryogenesis and homeostasis in adult animals.
  • the WNT pathway is comprised in general of a network of proteins that regulate the following processes: 1, the production and secretion of WNT proteins; 2, the binding of WNT with cellular receptors; and 3, the intracellular transduction of the biochemical responses triggered by the interaction (Mikels and Nusse, 2006; MacDonald, 2009; Moon, 2005).
  • Frizzled LRP5/6 results in a change in the amount of ⁇ -catenin that reaches the nucleus where; it interacts with TCF/LEF family transcription factors to promote transcription of specific genes.
  • the non-canonical WNT pathway transduced by a different set of intracellular proteins controls planai' cell polarity in insects and several processes such as gastrulation in vertebrates.
  • WNT signaling is also known for its roles in controlling pluripotency and differentiation of embryonic and adult stem cells (Nusse, 2008). For example, formation of the primitive streak during gastrulation was associated with localized WNT activation in the embryoid bodies (ten Berge, 2008).
  • the derivation of a number of cell types, such as heart cells, pancreatic beta cells, dopminergic neurons and liver hepatocytes from embryonic stem cells or iPS cells is influenced by WNT modulation (Yang, 2008; D'Amour, 2006; Inestrosa and Arenas, 2010; Sullivan, 2010).
  • the WNT pathway plays a particularly important role in skeletal tissue development such as osteogenesis and chondrogenesis (Hoeppner, 2009; Chun, 2008).
  • WNT signaling is also associated with neuro- regeneration of the adult central nervous system (Lie, 2005).
  • WNT pathway activity may arise from altered WNT pathway activity.
  • hyperactivation of the canonical WNT pathway can lead to aberrant cell growth (Reya and Clevers, 2005).
  • 90% of colorectal cancers are initiated by the loss of the adenomatosis polyposis coli (APC) gene, a suppressor of the WNT/p-catenin pathway (Kinzler and Vogelstein, 1996).
  • Increased expression of WNT proteins and loss of extracellular inhibitors that normally suppress WNT protein function may give rise to WNT-dependent tumors (Polakis, 2007).
  • the non-canonical WNT pathway has also been shown to play a role in the progression of certain cancers (Camilli and Weeraratna, 2010). More recently, WNT signaling is also implicated in cancer stem cells (Takahashi-Yanaga and Kahn, 2010).
  • cancers include but not limited to: lung (small cell and non-small cell), breast, prostate, carcinoid, bladder, scarcinoma, esophageal, ovarian, cervical, endometrial, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, desmoids, chronic myelocytic leukemia (AML), and chronic myelocytic leukemia (CML).
  • lung small cell and non-small cell
  • breast breast
  • prostate carcinoid
  • bladder scarcinoma
  • esophageal esophageal
  • ovarian cervical
  • endometrial mesothelioma
  • melanoma melanoma
  • osteosarcoma osteosarcoma
  • liposarcoma thyroid
  • desmoids chronic myelocytic leukemia
  • AML chronic myelocytic leukemia
  • CML chronic myelocytic leukemia
  • fibrosis include but are not limited to: lung fibrosis, such as idiopathic pulmonary fibrosis and radiation-induced fibrosis, renal fibrosis and liver fibrosis (Morrisey, 2003; Hwang, 2009; Cheng, 2008).
  • WNT signaling also contributes to the self-renewal and maintenance of HSC's, and dysfunctional WNT signaling is responsible for various disorders resulting from HSC's, such as leukemias and various other blood related cancers (Reya,, 2005). Accordingly, identification of methods and compounds that modulate the WNT- dependent cellular responses may offer an avenue for regulating physiological functions and therapeutic treatment of diseases associated with aberrant activity of the pathways.
  • the present invention generally provides a compound and a pharmaceutical composition thereof, while the compound is used as WNT signaling inhibitor, and the use of such compound for inhibiting WNT signaling pathway.
  • WNT signaling pathway or “WNT pathway” refers to the pathway by which binding of the WNT protein to cellular receptors results in changes of cell behavior.
  • the WNT pathway involves a variety of proteins including Frizzled, Disheveled, Axin, APC, GSK3P, ⁇ -catenin, LEF/TCF transcription factors, and molecules involved in the synthesis and secretion of WNT proteins.
  • proteins implicated in the secretion of functional WNTs include, but are not limited to wntless/evenness interrupted (Wls Evi), porcupine (Porcn), and Vps35p.
  • Wls Evi is a 7 pass transmembrane protein which resides in the Golgi apparatus and is required for secretion of Wg (drosophila) MOM-2 (c. elegans) and Wnt3A. It contains a conserved structural motif whose structure and function are both unknown.
  • Porcupine (Porcn) is a member of the membrane-bound O- acyltransferase (MBOAT) family of palmitoyl transferases. Fatty acid modification of Wnts is critical for their function. Wnts are pahnitoylated on one or two highly conserved sites. Inhibitors of Porcn may therefore block all functional Wnt signaling.
  • Vps35p is a subunit of a multiprotein complex called the retromer complex which is involved in intracellular protein trafficking. Vps35p functions in binding target proteins like WNTs for recruitment into vesicles.
  • WNT pathway inhibitor or “WNT signaling inhibitor” is a small organic molecule that inhibits WNT signaling activity and typically has a molecular weight of about 800 g/mol or less.
  • a method of inhibiting WNT pathway refers to methods of inhibiting known biochemical events associated with production of functional WNT proteins or with cellular responses to WNT proteins. As discussed herein, small organic molecules may inhibit WNT response in accordance with this definition.
  • WNT protein is a protein binds to Frizzled and LRP5/6 co-receptors so as to activate canonical or non-canonical WNT signaling.
  • WNT proteins include: WNT-1 (NM005430),
  • WNT-2 (NM003391), WNT-2B/WNT-13 (NM004185), WNT-3 (NM030753), WNT3a
  • WNT-4 (NM030761), WNT-5A (NM003392), WNT-5B (NM032642), WNT-6 (NM006522), W T-7A (NM004625), W T-7B (NM058238), NT-8A (NM058244), WNT-8B (NM003393), WNT-9A/WNT-14) (NM003395), WNT-9B/W T- 15 (NM003396), WNT-10A (NM025216), WNT-10B (NM003394), WNT-11 (NM004626), WNT-16 (NM016087).
  • WNT pathway disorder is a condition or disease state with aberrant WNT signaling.
  • the aberrant WNT signaling is a level of WNT signaling in a cell or tissue suspected of being diseased that exceeds the level of WNT signaling in a normal cell or tissue.
  • a WNT-mediated disorder includes cancer or fibrosis.
  • cancer refers to the pathological condition in humans that is characterized by unregulated cell proliferation. Examples include but are not limited to: carcinoma, lymphoma, blastoma, and leukemia. More particular examples of cancers include but are not limited to: lung (small cell and non-small cell), breast, prostate, carcinoid, bladder, gastric, pancreatic, liver (hepatocellular), hepatoblastoma, colorectal, head and neck squamous cell carcinoma, esophageal, ovarian, cervical, endometrial, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, desmoids, chronic myelocytic leukemia (AML), and chronic myelocytic leukemia (CML).
  • AML chronic myelocytic leukemia
  • CML chronic myelocytic leukemia
  • fibrosis refers to the pathological condition in humans that is typically characterized by uncontrolled proliferation of fibroblast cells and tissue hardening. Specific examples include but not limited to: lung fibrosis (idiopathic pulmonary fibrosis and radiation-induced fibrosis), renal fibrosis and liver fibrosis including liver cirrhosis.
  • “Inhibiting” or “treating” or “treatment” refers to reduction, therapeutic treatment and prophylactic or preventative treatment, wherein the objective is to reduce or prevent the aimed pathologic disorder or condition.
  • a cancer patient may experience a reduction in tumor size.
  • “Treatment” or “treating” includes (1) inhibiting a disease in a subject experiencing or displaying the pathology or symptoms of the disease, (2) ameliorating a disease in a subject that is experiencing or displaying the pathology or symptoms of the disease, and/or (3) affecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptoms of the disease.
  • the WNT pathway inhibitor may prevent growth and/or kill cancer cells, it may be cytostatic and/or cytotoxic.
  • therapeutically effective amount refers to an amount of a WNT pathway inhibitor effective to "treat" a WNT pathway disorder in a subject or mammal.
  • the therapeutically effective amount of the drug may either reduce the number of cancer cells, reduce the tumor size, inhibit cancer cell infiltration into peripheral organs, inhibit tumor metastasis, inhibit tumor growth to certain extent, and/or relieve one or more of the symptoms associated with the cancer to some extent.
  • Administration in combination with one or more further therapeutic agents includes simultaneous
  • the term “pharmaceutical combination” refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non- fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Examples are but not limited to: Gemcitabine, Irinotecan, Doxorubicin, i5-Fluorouracil, Cytosine arabinoside ("Ara-C"), Cyclophosphamide, Thiotepa, Busulfan, Cytoxin, TAXOL, Methotrexate, Cisplatin, Melphalan, Vinblastine and Carboplatin.
  • the present invention provides a compound as NT signaling inhibitor, which has the structure of Formula I:
  • Xi, X 2 , X 3 , 4 are independently CR 4 or N;
  • Y 2 , Y 3 are independently hydrogen, halo or CR 3 ;
  • Ri is morpholinyl, piperazinyl, quinolinyl, , aryl, C 1-6 heterocycle, 5 or 6 membered
  • R 2 is hydrogen, halo, morpholinyl, piperazinyl, quinolinyl,— ⁇ , aryl, Ci-gheterocycle, 5 c membered heteroaryl containing 1-2 heteroatoms selected from N, O and S;
  • 5 or 6 membered heteroaryl includes the following selected groups but not limited to:
  • Ri and R 2 could be independently and optionally substituted with 1-2 R4 groups;
  • R 3 is hydrogen, halo, cyano, Ci -6 alkyl, C 1-6 alkoxy optionally substituted with halo, amino, hydroxyl, alkoxy or cyano;
  • R4 is hydrogen, halo, C ⁇ alkoxy, -S(0) 2 R 5 , -C(0)OR 5 , -C(0)R S , -C(0)NR ⁇ ;R 7 , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which can be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano;
  • R 5 , R 6 and R 7 are independently hydrogen, Ci -6 alkyl, C 2-6 alkenyl or C 2 - 6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano;
  • Rg is hydrogen or Ci. 6 alkyl.
  • an H atom in any substituent groups encompasses all suitable isotopic variations, e.g., H, 2 H and 3 H.
  • atoms in any substituent groups encompasses all suitable isotopic variations, including but not limited to n C, I3 C, 14 C , 15 N, 17 0, 18 0, 35 S, 18 F, 36 I and/or 123 I.
  • example of the compound of the invention includes but is not limited to:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and at least one pharmaceutically acceptable carrier or diluent, wherein said compound is in free form or in a pharmaceutically acceptable salt form.
  • Such composition may be an oral composition, injectable composition or suppository.
  • the composition may be manufactured in a conventional manner by mixing, granulating or coating methods.
  • the composition is an oral composition and it may be a tablet or gelatin capsule.
  • the oral composition comprises the present compound together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets, together with c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragamayth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and if desired, d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) additives, e.g., absorbents, colorants, flavors, e.g.,
  • the composition is an injectable composition, and maybe an aqueous isotonic solution or suspension.
  • the composition is a suppository and may be prepared from fatty emulsion or suspension.
  • the composition is sterilized and/or contains adjuvant.
  • adjuvant can be preserving, stabilizing, wetting or emulsifying agent, solution promoter, salt for regulating the osmotic pressure, buffer and/or any combination thereof.
  • the composition may further contain other therapeutically valuable substances for different applications, like solubilizers, stabilizers, tonicity enhancing agents, buffers and/ or preservatives.
  • the composition may be a formulation suitable for transdermal application.
  • Such formulation includes an effective amount of the compound of the present invention and a carrier.
  • the carrier may include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • a transdermal device contain the formulation may also be used.
  • the transdermal device may be in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • a matrix transdermal formulation may also be used.
  • the composition may be a formulation suitable for topical application, such as to the skin and eyes, and may be aqueous solution, ointment, cream or gel well known in the art.
  • the present invention provides a method of inhibiting WNT secretion from a cell.
  • the present invention provides a method of inhibiting WNT signaling in a cell with an effective amount of the present compound.
  • the cell is contained within a mammal, and the administered amount is a therapeutically effective amount.
  • the inhibition of WNT signaling further results in the inhibition of the growth of the cell.
  • the cell is a cancer cell.
  • the cell is a fibrogenic cell.
  • Cell proliferation is measured by using methods known to those skilled in the art.
  • a convenient assay for measuring cell proliferation is the CellTiter-GloTM Assay commercially available from Promega (Madison, WI).
  • the assay procedure involves adding the CellTiter-Glo® reagent to cells cultured on multi-well dishes.
  • the luminescent signal measured by a luminometer or an imaging device, is proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in culture.
  • cell proliferation may also be measured using colony formation assays known in the art.
  • the present invention also provides a method for treating cancers or fibroses related to the WNT signaling pathway with an effective amount of the present compound.
  • Those skilled in the art would readily be able to determine whether a cancer is related to the Wnt pathway by analyzing cancer cells using one of several techniques known in the art. For example, one could examine cancer cells for aberrations in the levels of proteins or mRNAs involved in Wnt signaling using immune and nucleic acid detection methods.
  • Cancers or fibroses related to the Wnt pathway include those in which activity of one or more components of the Wnt signaling pathways are upregulated from basal levels.
  • inhibiting the Wnt pathway may involve inhibiting Wnt secretion.
  • inhibiting the Wnt pathway may involve inhibiting components downstream of the cell surface receptors.
  • inhibition of Wnt secretion may involve inhibiting the activity of any of the proteins implicated in the secretion of functional WNTs.
  • the invention provides a method for treating a WNT pathway disorder in a subject suffering from the disorder by adrriinistering to the subject a therapeutically effective amount of a WNT inhibitor.
  • the disorder is a cell proliferative disorder associated with aberrant, e.g., increased, activity of WNT signaling.
  • the disorder results from increased amount of a WNT protein.
  • the cell proliferative disorder is cancer, include but are not limited to: lung (small cell and non-small cell), breast, prostate, carcinoid, bladder, gastric, pancreatic, liver (hepatocellular), hepatoblastoma, colorectal, head cancer and neck squamous cell carcinoma, esophageal, ovarian, cervical, endometrial, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, desmoids, chronic myelocytic leukemia (AML), and chronic myelocytic leukemia (CML).
  • lung small cell and non-small cell
  • breast breast
  • prostate carcinoid
  • bladder gastric
  • pancreatic liver
  • hepatoblastoma colorectal
  • head cancer and neck squamous cell carcinoma esophageal
  • ovarian cervical
  • endometrial mesothelioma
  • the cell proliferative disorder is fibrosis, include but are not limited to: lung fibrosis, such as idiopathic pulmonary fibrosis and radiation-induced fibrosis, renal fibrosis and liver fibrosis including liver cirrhosis.
  • lung fibrosis such as idiopathic pulmonary fibrosis and radiation-induced fibrosis
  • renal fibrosis and liver fibrosis including liver cirrhosis.
  • the disorder is osteoarthritis, Parkinson's disease, retinopathy, macular degeneration.
  • the compound of the present invention could be administered in a therapeutically effective amount via any acceptable way known in the art singly.
  • the therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the satisfactory result is indicated to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg/kg per body weight of the subject.
  • the indicated daily dosage for larger mammal as human is in the range from about 0.5mg to about lOOmg.
  • the compound is administered in divided doses up to four times a day or in retard form.
  • suitable unit dosage forms for oral administration comprise from ca. 1 to 100 mg active ingredient.
  • the compound of the present invention may be adrninistered in a therapeutically effective amount as the active ingredient in combination with one or more therapeutic agents, such as pharmaceutical combinations.
  • therapeutic agents such as pharmaceutical combinations.
  • the dosage of the co-administered compounds could vary depending on the type of co-drug employed, the specific drug employed, the condition being treated and so forth.
  • the compound of the present invention or the composition thereof may be administered by any conventional route. In one embodiment, it is administered enterally, such as orally, and in the form of tablets or capsules. In another embodiment, it is administered parenterally and in the form of injectable solutions or suspensions. In yet another embodiment, it is administered topically and in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • the invention also provides a pharmaceutical combination, preferably, a kit, comprising a) a first agent which is the compound of the present invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a kit comprising a) a first agent which is the compound of the present invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit may comprise instructions for its administration.
  • the combination of the present invention may be used in vitro or in vivo.
  • the desired therapeutic benefit of the administration may be achieved by contacting cell, tissue or organism with a single composition or pharmacological formulation that includes the compound of the present invention and one or more agents, or by contacting the cell with two or more distinct compositions or formulations, wherein one composition includes one agent and the other includes another.
  • the agents of the combination may be administered at the same time or separately within a period of time.
  • the separate administration can result in a desired therapeutic benefit.
  • the present compound may precede, be co -current with and /or follow the other agents by intervals ranging from rninutes to weeks.
  • a person skilled in the art could generally ensure the interval of the time of each delivery, wherein the agents administered separately could still be able to exert an advantageously combined effect on the cell, tissue or organism.
  • one may contact the cell, tissue or organism with two, three, four or more modalities substantially simultaneously as the candidate substance, i.e., with less than about one minute.
  • one or more agents may be administered about between lmintue to 14 days.
  • the present provides a process for preparing the compound of the present invention or the salts or derivatives thereof.
  • the compound having Formula (I) may be prepared following any one of the synthetic methodologies described in Examples below.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, may be protected to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice (see e.g., T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991).
  • Suitable leaving groups for use in the synthetic methodologies described include halogen leaving groups and other conventional leaving groups known in the art.
  • the leaving group is chloro or bromo.
  • the compound of the invention or the salts thereof may also be obtainable in the form of hydrates, or their crystals may include for example the solvent used for crystallization (present as solvates).
  • Salts can usually be converted to compounds in free form by treating with suitable basic agents, preferably with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, more preferably with potassium carbonate or sodium hydroxide.
  • suitable basic agents preferably with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, more preferably with potassium carbonate or sodium hydroxide.
  • a compound of the invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid, such as hydrochloric acid.
  • any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate.
  • Salts of the present compound with a salt-forming group may be prepared in a manner known in the art. Acid addition salts of compound of Formula (I) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. Pharmaceutically acceptable salts of the compound of the invention may be formed as acid addition salts from compound of Formula (I) with a basic nitrogen atom with organic or inorganic acids.
  • suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • suitable organic acids include, but are not limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,-malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethan
  • compound of the present invention in unoxidized form may be prepared from N-oxides of compound of the invention by treating with a reducing agent in a suitable inert organic solvent at 0 to 80°C.
  • a reducing agent is sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like.
  • the invert organic solvent is acetonitrile, ethanol, aqueous dioxane, or the like.
  • prodrug derivatives of the compound of the present invention may be prepared by methods known in the art (for further details see Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • an appropriate prodrug may be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent such as 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • protected derivatives of the compound of the present invention may be made by means known in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal may be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
  • compound of the present invention may be prepared as their individual stereoisomers.
  • the process includes reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • Resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compound of the present invention, or by using dissociable complexes such as crystalline diastereomeric salts.
  • Diastereomers have distinct physical properties presented by melting points, boiling points, solubilities, reactivity, etc., and may be readily separated by taking advantage of these dissimilarities.
  • the diastereomers may be separated by fractionated crystallization, chromatography, or by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture may be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • a pharmaceutically acceptable salt may be converted from the compound of the present invention.
  • a pharmaceutically acceptable N-oxide may be converted from an unoxidized form of the compound the present invention
  • an individual isomer of the compound of the present invention is resolved from a mixture of isomers; and optionally a pharmaceutically acceptable prodrug derivative may be converted from a non- derivatized compound of the present invention.
  • the present invention is further exemplified, but not limited, by the following and Exampli illustrate the preparation of the compounds of the invention.
  • the reaction mixture in the pressure tube was heated up to 130°C for lh, and then cooled down to RT.
  • the mixture was poured in water, extracted by EA for three times.
  • the combined organic layer was washed with brine, dried over Na 2 S04, filtered and concentrated under the vacuum.
  • ⁇ 3 ⁇ 3 mouse fibroblast cells (American Type Culture Collection, Manassas, VA) were transfected with a plasmid containing a luciferase gene driven by 5 copies of TCF elements.
  • Stale cells selected with 1 g lnL of Zeocin (Gibco/lnvitrogen, Carlsbad, CA) are cultured in Dulbecco's modified Eagle's medium (Invitrogen, Carlsbad, CA) supplemented with 10% FBS (Invitrogen), 50 unit mL penicillin and 50 ⁇ g/mL of streptomycin (Invitrogen) at 37°C with 5% C02 in air atmosphere.
  • Suspension HEK293 cells were transfected with a plasmid containing full-length human WNT-3a cDNA sequence driven by a CMV promoter, and stable cells were selected in FreeStyle 293 medium (Invitrogen) supplemented with lOOug mL G418.
  • FreeStyle 293 medium Invitrogen
  • the NIH3T3 TCF-Luc cells and 293 WNT3a cells were co-cultured in a 96-well plate with DMEM medium supplemented with 0.5% FBS. After 16 hours, the firefly luciferase activities are measured with the Steady-GloTM Luciferase Assay System (Promega).
  • the cells were treated with different concentrations of compounds of this invention during the co-culture.
  • the IC50s were defined as the concentration when the compounds reduce the luminescence intensity by 50%.
  • CellTiter Glo assay is next performed in a duplicate plate.
  • results of such mechanistic studies showed that some of the active compounds in this invention inhibit WNT pathway activation at a point before the WNT-3a interaction with the receptors, as they did not inhibit the TCF reporter gene activation by recombinant WNT-3a protein.
  • the candidates of such action include, but are not limited to wntless/evenness interrupted (Wls/Evi), porcupine (Porcn), and Vps35p.
  • Compounds that inhibit Wnt secretion and intracellular signal transduction are expected to inhibit proliferation of cancer cells that depend on autocrine Wnt signaling.
  • Compounds are evaluated by using standard assays on the Wnt dependent cell lines known in the published literature: PA-1 (ovarian teratocarcinoma cancer), MDA-MB-157 (breast cancer), Saos-2 (osteosarcoma) and SNU1076 (head and neck squamous carcinoma). Effects of the inhibitors are seen in these cell lines, further confirming the activities expected for the compounds.
  • Boonen RA van Tijn P, Zivkovic D. Wnt signaling in Alzheimer's disease: up or down, that is the question. Ageing Res Rev. 2009 Apr;8(2):71-82.
  • Kansara M et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest. 2009 Apr; 119(4): 837-51

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Abstract

La présente invention concerne un composé en tant qu'inhibiteur des voies de transduction du signal WNT, ainsi qu'une composition comprenant le composé. En outre, la présente invention concerne également l'utilisation du composé et la méthode d'inhibition des voies de transduction du signal WNT.
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WO2014147182A2 (fr) 2013-03-20 2014-09-25 Bayer Pharma Aktiengesellschaft Nouveaux composés
CN105348298A (zh) * 2014-07-04 2016-02-24 沈阳中化农药化工研发有限公司 取代芳基吡啶类化合物及其用途
WO2016131794A1 (fr) 2015-02-20 2016-08-25 Bayer Pharma Aktiengesellschaft Dérivés de 3-carbamoylphényl-4-carboxamide et d'isophtalamide en tant qu'inhibiteurs de la voie de signalisation wnt
WO2016131810A1 (fr) 2015-02-20 2016-08-25 Bayer Pharma Aktiengesellschaft Dérivés de n-phényl-(morpholin-4-yl ou pipérazinyl)acétamide et leur utilisation comme inhibiteurs des voies de signalisation wnt
WO2016131808A1 (fr) 2015-02-20 2016-08-25 Bayer Pharma Aktiengesellschaft Dérivés de 1,3,4-thiadiazol-2-yl-benzamide utilisés en tant qu'inhibiteurs de la voie de signalisation wnt
JPWO2015083833A1 (ja) * 2013-12-06 2017-03-16 カルナバイオサイエンス株式会社 新規キナゾリン誘導体
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10130633B2 (en) 2013-03-20 2018-11-20 Bayer Pharma Aktiengesellschaft Compounds
WO2019157085A3 (fr) * 2018-02-06 2020-04-16 Vanderbilt University Inhibition de la signalisation wnt/bêta-caténine dans le traitement de l'arthrose
EP4223305A4 (fr) * 2020-10-02 2024-05-01 Osaka University Inhibiteur de la voie de signalisation wnt

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
US20130245063A1 (en) * 2011-06-10 2013-09-19 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10106529B2 (en) 2011-06-10 2018-10-23 Calcimedia, Inc. Compounds that modulate intracellular calcium
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2014147182A2 (fr) 2013-03-20 2014-09-25 Bayer Pharma Aktiengesellschaft Nouveaux composés
US10130633B2 (en) 2013-03-20 2018-11-20 Bayer Pharma Aktiengesellschaft Compounds
JPWO2015083833A1 (ja) * 2013-12-06 2017-03-16 カルナバイオサイエンス株式会社 新規キナゾリン誘導体
EP3078660A4 (fr) * 2013-12-06 2017-05-17 Carna Biosciences Inc. Nouveau dérivé quinazoline
US9682961B2 (en) 2013-12-06 2017-06-20 Carna Biosciences, Inc. Quinazoline derivative
CN105348298A (zh) * 2014-07-04 2016-02-24 沈阳中化农药化工研发有限公司 取代芳基吡啶类化合物及其用途
WO2016131808A1 (fr) 2015-02-20 2016-08-25 Bayer Pharma Aktiengesellschaft Dérivés de 1,3,4-thiadiazol-2-yl-benzamide utilisés en tant qu'inhibiteurs de la voie de signalisation wnt
WO2016131810A1 (fr) 2015-02-20 2016-08-25 Bayer Pharma Aktiengesellschaft Dérivés de n-phényl-(morpholin-4-yl ou pipérazinyl)acétamide et leur utilisation comme inhibiteurs des voies de signalisation wnt
WO2016131794A1 (fr) 2015-02-20 2016-08-25 Bayer Pharma Aktiengesellschaft Dérivés de 3-carbamoylphényl-4-carboxamide et d'isophtalamide en tant qu'inhibiteurs de la voie de signalisation wnt
WO2019157085A3 (fr) * 2018-02-06 2020-04-16 Vanderbilt University Inhibition de la signalisation wnt/bêta-caténine dans le traitement de l'arthrose
EP4223305A4 (fr) * 2020-10-02 2024-05-01 Osaka University Inhibiteur de la voie de signalisation wnt

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