WO2008060283A1 - 4-anilino-3-quinolinecarbonitriles utilisables pour le traitement de la leucémie aigue myéloblastique (lam) - Google Patents

4-anilino-3-quinolinecarbonitriles utilisables pour le traitement de la leucémie aigue myéloblastique (lam) Download PDF

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Publication number
WO2008060283A1
WO2008060283A1 PCT/US2006/044582 US2006044582W WO2008060283A1 WO 2008060283 A1 WO2008060283 A1 WO 2008060283A1 US 2006044582 W US2006044582 W US 2006044582W WO 2008060283 A1 WO2008060283 A1 WO 2008060283A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
anilino
carbonitrile
methyl
compound
Prior art date
Application number
PCT/US2006/044582
Other languages
English (en)
Inventor
Frank Boschelli
Original Assignee
Wyeth
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth filed Critical Wyeth
Priority to PCT/US2006/044582 priority Critical patent/WO2008060283A1/fr
Priority to PCT/US2007/084545 priority patent/WO2008064004A2/fr
Publication of WO2008060283A1 publication Critical patent/WO2008060283A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/08—Aza-anthracenes
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the claimed invention is directed to a method of using 4-anilino-3 ⁇ quinolinecarbonitriles to treat, inhibit, or prevent acute myelogenous leukemia, also called acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • STAT transcription
  • IL-3 growth factors and cytokines, such as IL-3, GM-CSF, erythropoietin, and thrombopoietin, effect responses through JAK/STAT signaling pathways, activating primarily Stat3 and Stat5 in hematopoietic progenitor cells.
  • cytokines such as IL-3, GM-CSF, erythropoietin, and thrombopoietin
  • STAT proteins effect responses through JAK/STAT signaling pathways, activating primarily Stat3 and Stat5 in hematopoietic progenitor cells.
  • Constitutive activation of STAT proteins has also been reported in cells transformed by diverse oncoproteins and tumor viruses, such as Src and AbI tyrosine kinases.
  • the protein tyrosine kinases consist of functionally related receptor and nonreceptor signaling enzymes regulating cell growth, activation, differentiation, development, and transformation through phosphorylation of specific tyrosine residues.
  • the receptor tyrosine kinases such as epidermal growth factor receptor (EGFR)
  • EGFR epidermal growth factor receptor
  • the nonreceptor tyrosine kinases such as Src and AbI, are soluble cytoplasmic enzymes with multiple regulatory and protein-binding domains.
  • the Src tyrosine kinase family is a group of 9 nonreceptor tyrosine kinases defined by both functional and sequence similarity. Three members of this family are widely expressed: Src, Yes, and FynB. The other 6 members, Lck, Lyn, FynT, Fgr, Hck, and BIk, are predominantly expressed in hematopoietic cells. Extensive reviews on structure and function of nonreceptor protein tyrosine kinases and their relevance in human cancers have been published.
  • Src nonreceptor protein tyrosine kinase is the prototype of the Src family. Src is a key downstream component of pathways mediated by growth factor receptors and G-protein coupled receptors, and is believed to coordinate signals from these various pathways.
  • the list of intracellular target proteins known to be phosphorylated by Src-famiiy kinases is large and continues to grow, including integrins, adhesion kinases, cadherins, stat3, stat5, cortactin, ezrin, focal adhesion proteins (FAK), and many others.
  • Src is upregulated in most cancers, including the vast majority of hematological malignancies. Based on the above observations, compounds that inhibit Src activity may be useful in treating patients with AML. BRIEF SUMMARY OF INVENTION
  • the claimed invention is directed to a method of treating, inhibiting, or preventing AML, comprising providing a therapeutically effective amount of a compound of Formula (I):
  • Ri, R 2 , R3, and R 4 are each independently hydrogen, a halogen, an alkyl, or an alkoxy;
  • R 7 is -0-(CH 2 X 1 -RiO, -furyl-(CH 2 ) n -Rio, or -pyridinyl-(CH 2 ) n -R 10 , wherein n is 0-3, and Ri 0 is an unsubstituted or alkyl-substituted piperazinyl or morpholinyl; and
  • R 8 is an alkoxy
  • This invention is also directed to a method of treating, inhibiting, or preventing AML, comprising providing a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
  • the compounds of Formula (I) may be delivered alone or in combination with one or more other compounds used to treat AML.
  • This invention is directed to a method of treating, inhibiting, or preventing AML comprising providing a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts thereof.
  • inhibiting refers to retarding, suppressing, or stopping malignant cell proliferation, presumably by blocking or suppressing phosphorylation catalyzed by Src.
  • preventing refers to averting or forestalling the development of malignant or tumoric growths by prophylactic treatment, or to impede, inhibit, or cease further progression of the disease.
  • the term “therapeutically effective amount” refers to an amount of compound sufficient to cure, inhibit, or ameliorate symptoms of AML.
  • alkyl includes both straight and branched alkyl moieties, preferably having 1 to 8 carbons.
  • alkoxy is defined as alkyl-O-.
  • halogen may be selected from chloride, bromide and fluoride moieties.
  • alkyl- substituted piperazinyl or “alkyl-substituted morpholinyl” means the nitrogen of the piperazinyl moiety may be substituted with an alkyl moiety or one or more of the ring carbons of either piperazinyl or morpholinyl may be substituted with an alkyl moiety.
  • a compound of Formula (I) may be provided orally, topically, by intralesional, intraperitoneal, intramuscular or intravenous injection, by infusion, or by nasal, anal, vaginal, sublingual, uretheral, transdermal, intrathecal, ocular, otic, or liposome-mediated delivery.
  • the compound is in the form of the unit dose.
  • Suitable unit dose forms include tablets, capsules, and powders, in sachets or vials.
  • Such unit dose forms may contain from about 0.1 to about 300 mg of a compound of Formula (I), and preferably from about 2 to about 200 mg.
  • Still further preferred unit dosage forms contain about 50 to about 150 mg of a compound of Formula (I).
  • a compound of Formula (I) may be administered from 1 to 6 times a day, and more usually from 1 to 4 times a day.
  • the effective amount will be known to one of skill in the art, and will depend upon the form of the compound, the purpose of administration, and the like.
  • One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of a compound of Formula (I) in bioassays and thus determine what dosage to administer.
  • salts are those derived from such organic and inorganic acids as: acetic, lactic, carboxylic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
  • This invention is also directed to a method of treating, inhibiting, or preventing AML, comprising providing a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
  • the carrier may be, for example, a diluent, an aerosol, a topical carrier, an aqueous solution, a nonaqueous solution, or a solid.
  • the carrier may also be a polymer or a toothpaste.
  • a carrier in this invention encompasses any of the standard pharmaceutically accepted carriers, such as water, phosphate buffered saline (PBS) solution, acetate buffered saline solution, emulsions, such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules.
  • PBS phosphate buffered saline
  • emulsions such as an oil/water emulsion or a triglyceride emulsion
  • various types of wetting agents such as water, phosphate buffered saline (PBS) solution, acetate buffered saline solution, emulsions, such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules.
  • the compositions containing the compound of Formula (I) may be formulated with conventional excipients, such as fillers, dis
  • such compounds When provided orally or topically, such compounds would be provided to a subject by delivery in different carriers.
  • such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, or glycols.
  • the specific carrier would need to be selected based upon the desired method of delivery.
  • PBS could be used for intravenous or systemic delivery
  • vegetable fats, creams, salves, ointments, or gels may be used for topical delivery.
  • a compound of Formula (I) may be delivered together with suitable diluents, preservatives, solubilizers, emulsif ⁇ ers, adjuvants and/or carriers useful in treatment or prevention of neoplasm.
  • suitable diluents for example, Tris-HCl, acetate, or phosphate
  • pH and ionic strength additives such as albumins or gelatin to prevent absorption to surfaces
  • detergents for example, TWEEN 20, TWEEN 80, PLURONIC F68, or bile acid salts
  • solubilizing agents for example, glycerol or polyethylene glycerol
  • antioxidants for example ascorbic acid or sodium metabisulfate
  • preservatives for example, thimerosal, benzyl alcohol or parabens
  • bulking substances or tonicity modifiers for example, lactose or mannitol
  • compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition.
  • the choice of compositions will depend on the physical and chemical properties of the compound capable of treating or preventing a neoplasm.
  • the compound of Formula (I) may be delivered locally via a capsule that allows a sustained release of the compound over a period of time.
  • Controlled or sustained release compositions include formulation in lipophilic depots (for example, fatty acids, waxes, or oils).
  • the present invention further provides a method of using a compound of Formula (I) as an active therapeutic substance for treating, inhibiting, or preventing AML.
  • the compound of Formula (I) may be delivered alone or in combination with other compounds used to treat AML.
  • Such compounds include but are not limited to daunorubicin, cytarabine, thioguanine, idarubicin, methotrexate, all- trans retinoic acid, mercaptopurine, mylotarg, etoposide, arsenic trioxide, and mitoxantrone.
  • Preferred compounds for practicing the method of and/or for use in a composition of this invention are 4-[(2,4-dichloro-5-methoxy-phenyl)amino]-6- methoxy-7-[3-(4-methyl-piperazin-l-yl)-propoxy]-quinoline-3-carbonitrile and pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) may be prepared according to the methods disclosed in U.S. Patent Nos. 6,002,008 and 6,780,996, and such methods are hereby incorporated by reference.
  • Table 1 shows proliferation assay results obtained upon treating human AML cell lines with several 4-anilino-3-quinolinecarbonitriles of Formula (I). These compounds were prepared according to previously published methods (Boschelli, D. H., et. al., J. Med. Chem., 44, 3965 (2001); Boschelli, D. H., et. al., J. Med. Chem., 44, 822 (2001); Boschelli, D. H., et. al., Bioorg. Med. Chem. Lett., 13, 3797 (2003); Boschelli, D. H., et. al., J. Med. Chem., 47, 1599 (2004); and Ye, F.
  • IC 50 is the concentration of test compound needed to reduce the total amount of cell proliferation by 50%.
  • 4-an ⁇ lino-3- quinolinecarbonitriles are useful in treating, inhibiting, or preventing AML by suppressing proliferation of malignant cells, at least in part by inhibiting Src- catalyzed phosphorylation of cellular proteins. Therefore, administration of a therapeutically effective amount of a compound of Formula (I) may prevent or inhibit AML by suppressing malignant cell proliferation, or may treat a human already suffering from AML by preventing or inhibiting further progression of the disease.
  • the growth medium for U937 cells is: RPMI 1640 supplemented with glutamine, 10% fetal bovin serum, and 50 ⁇ g/ml of gentamicin.
  • the compounds described herein may represent a novel therapy for AML.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention revendiquée concerne un procédé de traitement, d'inhibition ou de prévention de la leucémie aiguë myéloblastique, également connue sous le nom de leucémie aiguë myéloïde (LAM), au moyen de 4-anilino-3-quinolinecarbonitriles.
PCT/US2006/044582 2006-11-16 2006-11-16 4-anilino-3-quinolinecarbonitriles utilisables pour le traitement de la leucémie aigue myéloblastique (lam) WO2008060283A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2006/044582 WO2008060283A1 (fr) 2006-11-16 2006-11-16 4-anilino-3-quinolinecarbonitriles utilisables pour le traitement de la leucémie aigue myéloblastique (lam)
PCT/US2007/084545 WO2008064004A2 (fr) 2006-11-16 2007-11-13 4-anilino-3-quinolinecarbonitriles destinés au traitement de la leucémie aiguë myélogène (lam)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2006/044582 WO2008060283A1 (fr) 2006-11-16 2006-11-16 4-anilino-3-quinolinecarbonitriles utilisables pour le traitement de la leucémie aigue myéloblastique (lam)

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WO2008060283A1 true WO2008060283A1 (fr) 2008-05-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064004A2 (fr) * 2006-11-16 2008-05-29 Wyeth 4-anilino-3-quinolinecarbonitriles destinés au traitement de la leucémie aiguë myélogène (lam)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780996B2 (en) * 2002-04-30 2004-08-24 Wyeth Holdings Corporation Process for the preparation of 7-substituted-3 quinolinecarbonitriles
US20050101780A1 (en) * 2003-11-06 2005-05-12 Wyeth 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780996B2 (en) * 2002-04-30 2004-08-24 Wyeth Holdings Corporation Process for the preparation of 7-substituted-3 quinolinecarbonitriles
US20050101780A1 (en) * 2003-11-06 2005-05-12 Wyeth 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064004A2 (fr) * 2006-11-16 2008-05-29 Wyeth 4-anilino-3-quinolinecarbonitriles destinés au traitement de la leucémie aiguë myélogène (lam)
WO2008064004A3 (fr) * 2006-11-16 2009-02-26 Wyeth Corp 4-anilino-3-quinolinecarbonitriles destinés au traitement de la leucémie aiguë myélogène (lam)

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