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Azaindole kinase inhibitorsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Three Nitrogens And Three Carbon Atoms, Asymmetrical (e.g., 1,2,4-triazine, Etc.), Polycyclo Ring System Having The Hetero Ring As One Of The CyclosAzaindole kinase inhibitors description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060058304, Azaindole kinase inhibitors. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a divisional of application Ser. No. 10/622,593 filed on Jul. 18, 2003, which claims the priority benefit of U.S. Provisional Application No. 60/397,256 filed Jul. 19, 2002 and U.S. Provisional Application No. 60/447,213 filed Feb. 13, 2003, the disclosures of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] This invention relates to compounds that inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, which are associated with signal transduction pathways operating through growth factors and anti-angiogenesis receptors such as VEGFR-2. BACKGROUND OF THE INVENTION [0003] Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing, obesity and several components of female reproductive function. Undesirable or pathological angiogenesis had been associated with disease states including diabetic retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma, asthma, cancer and metastatic disease (Fan et al, 1995, Trend Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). Alteration of vascular permeability is thought to play a role in both normal and pathophysiological processes (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Senger et al, 1993 Cancer and Metastasis Reviews, 12: 303-324). [0004] Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular proteins, leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised of the fms-like tyrosine kinase receptor, Flt or Flt1 (VEGFR-1), the kinase insert domain-containing receptor, KDR (also referred to as Flk-1 or VEGFR-2), and another fms-like tyrosine kinase receptor, Flt4 (VEGFR-3). Two of these related RTKs, Flt and KDR, have been shown to bind vascular endothelial growth factor (VEGF) with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells had been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes. VEGF, along with acidic and basic fibroblast growth factor (aFGF & bFGF) have been identified as having in vitro endothelial cell growth promoting activity. It is noted that aFGF and bFGF bind to and activate the receptor tyrosine kinase termed FGFR-1. By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024). [0005] In adults, endothelial cells have a low proliferation index except in cases of tissue remodeling, such as wound healing and the female reproductive cycle, and adipogenesis. However in pathological states such as cancer, inherited vascular diseases, endometriosis, psoriasis, arthritis, retinopathies and atherosclerosis, endothelial cells are actively proliferating and organizing into vessels. Upon exposure to angiogenic stimuli with growth factors such as VEGF and bFGF, endothelial cells re-enter the cell cycle, proliferate, migrate and organize into a three-dimensional network. It is now widely accepted that the ability of tumors to expand and metastasize is dependent upon the formation of this vascular network. [0006] Binding of VEGF or bFGF to their corresponding receptor results in dimerization, autophosphorylation on tyrosine residues and enzymatic activation. These phosphotyrosine residues serve as "docking" sites for specific downstream signaling molecules and enzymatic activation results in EC activation. Disruption of these pathways should inhibit endothelial cell activation. Disruption of the FGFR-1 pathway should also affect tumor cell proliferation since this kinase is activated in many tumor types in addition to proliferating endothelial cells. Finally, recent evidence also suggests that disruption of VEGF signaling inhibits endothelial cell migration, a critical process in vascular network formation. [0007] The over-expression and activation of VEGFR-2 and FGFR-1 in tumor-associated vasculature has suggested a role for these molecules in tumor angiogenesis. Angiogenesis and subsequent tumor growth is inhibited by antibodies directed against VEGF ligand and VEGF receptors, and by truncated (lacking a transmembrane sequence and cytoplasmic kinase domain) soluble VEGFR-2 receptors. Dominant mutations introduced into either VEGFR-2 or FGFR-1 which result in a loss of enzymatic activity inhibits tumor growth in vivo. Antisense targeting of these receptors or their cognate ligands also inhibits angiogenesis and tumor growth. Recent evidence has elucidated, in part, the temporal requirements of these receptors in tumor growth. It appears that VEGF signaling is critical in early tumor growth and bFGF is more important at a later time associated with tumor expansion. DETAILED DESCRIPTION OF THE INVENTION [0008] In accordance with the present invention, compounds of formula I, their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof, inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2. In formula I and throughout the specification, the above symbols are defined as follows: [0009] Z is selected from O, S, N, OH, or Cl, with the provisos that when Z is O or S, R.sup.41 is absent and when Z is OH or Cl, both R.sup.41 and R.sup.42 are absent; [0010] X and Y are independently selected from O, OCO, S, SO, SO.sub.2, CO, CO.sub.2, NR.sup.10, NR.sup.11CO, NR.sup.12CONR.sup.13, NR.sup.14CO.sub.2, NR.sup.15SO.sub.2, NR.sup.16SO.sub.2NR.sup.17, SO.sub.2NR.sup.18, CONR.sup.19, halogen, nitro, cyano, or X or Y are absent; [0011] R.sup.1 is hydrogen, CH.sub.3, OH, OCH.sub.3, SH, SCH.sub.3, OCOR.sup.21, SOR.sup.22, SO.sub.2R.sup.23, S.sub.2NR.sup.24R.sup.25, CO.sub.2R.sup.26, CONR.sup.27R.sup.28, NH.sub.2, NR.sup.29SO.sub.2NR.sup.30R.sup.31, NR.sup.32SO.sub.2R.sup.33, NR.sup.34COR.sup.35, NR.sup.36CO.sub.2R.sup.37, NR.sup.38CONR.sup.39R.sup.40, halogen, nitro, or cyano; [0012] R.sup.2 and R.sup.3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; with the proviso that when X is halo, nitro or cyano, R.sup.2 is absent, and, when Y is halo, nitro or cyano, R.sup.3 is absent; [0013] R.sup.6 is H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, NR.sup.7R.sup.8, OR.sup.9 or halogen; [0014] R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21R.sup.24, R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30, R.sup.31, R.sup.32, R.sup.34, R.sup.35, R.sup.36, R.sup.38, R.sup.39 and R.sup.40 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, or substituted heterocyclo; [0015] R.sup.22, R.sup.23, R.sup.33 and R.sup.37 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, or substituted heterocyclo; [0016] R.sup.42 is (R.sup.43).sub.n wherein n equals 0, 1 or 2 and each R.sup.43 is independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; and [0017] R.sup.44 is methyl, or hydrogen, with the further provisos that: [0018] a. R.sup.2 may not be hydrogen if X is SO, SO.sub.2, NR.sup.13CO.sub.2, or NR.sup.14SO.sub.2; and [0019] b. R.sup.3 may not be hydrogen if Y is SO, SO.sub.2, NR.sup.13CO.sub.2, or NR.sup.14SO.sub.2. [0020] In a preferred embodiment R.sup.1 is hydrogen or methyl; R.sup.6 is hydrogen; R.sup.3 is lower alkyl; and Z is oxygen or nitrogen. [0021] In another preferred embodiment R.sup.1 is hydrogen; R.sup.3 is lower alkyl; Y is absent; X is oxygen or nitrogen; R.sup.43 is fluoro or hydrogen; and R.sup.44 is hydrogen or methyl. [0022] In yet another preferred embodiment X is oxygen; R.sup.2 is a substituted alkyl and R.sup.43 is fluoro. [0023] In yet another preferred embodiment X is absent; R.sup.2 is a substituted hetrocyclo, substituted heterocyclo, heteroaryl, substituted heteroaryl, and Z is nitrogen. [0024] Preferred compounds of the invention include [0025] 4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2- ,4]triazin-6-ol, [0026] (R)-1-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-- f][1,2,4]triazin-6-yloxy]-propan-2-ol, [0027] (S)-1-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1- -f][1,2,4]triazin-6-yloxy]-propan-2-ol, [0028] (R)-1-[4-(4-Fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-py- rrolo[2,1-f][1,2,4]triazin-6-yloxy]-propan-2-ol, [0029] (R)-2-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-- f][1,2,4]triazin-6-yloxy]-1-methylethylamine, [0030] (R)-2-[4-(4-Fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyr- rolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methyl-ethylamine, [0031] 2-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1- ,2,4]triazin-6-yloxy]-ethylamine, [0032] (4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-[5-isopropyl-6-(3-methyl-[1,2,4]- oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine, [0033] (4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-[5-isopropyl-6-(5-methyl-[1,3,4]- oxadiazol-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine, [0034] (4-Fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-[5-isopropyl-6-(5-methy- l-[1,3,4]oxadiazol-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine, and [0035] [5-Isopropyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolo[2,1-f][1,2- ,4]triazin-4-yl]-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-amine. [0036] The invention also provides a pharmaceutical composition comprising a compound of formula I or II and a pharmaceutically acceptable carrier. [0037] The invention also provides a pharmaceutical composition comprising a compound of formula I or II in combination with pharmaceutically acceptable carrier and an anti-cancer or cytotoxic agent. In a preferred embodiment said anti-cancer or cytotoxic agent is selected from the group consisting of linomide; inhibitors of integrin .alpha.v.beta.3 function; angiostatin; razoxane; tamoxifen; toremifene; raloxifene; droloxifene; iodoxifene; megestrol acetate; anastrozole; letrozole; borazole; exemestane; flutamide; nilutamide; bicalutamide; cyproterone acetate; gosereline acetate; leuprolide; finasteride; metalloproteinase inhibitors; inhibitors of urokinase plasminogen activator receptor function; growth factor antibodies; growth factor receptor antibodies such as Avastin.RTM. (bevacizumab) and Erbitux.RTM. (cetuximab); tyrosine kinase inhibitors; serine/threonine kinase inhibitors; methotrexate; 5-fluorouracil; purine; adenosine analogues; cytosine arabinoside; doxorubicin; daunomycin; epirubicin; idarubicin; mitomycin-C; dactinomycin; mithramycin; cisplatin; carboplatin; nitrogen mustard; melphalan; chlorambucil; busulphan; cyclophosphamide; ifosfamide nitrosoureas; thiotepa; vincristine; Taxol.RTM. (paclitaxel); Taxotere.RTM. (docetaxel); epothilone analogs; discodermolide analogs; eleutherobin analogs; etoposide; teniposide; amsacrine; topotecan; flavopyridols; biological response modifiers and proteasome inhibitors such as Velcade.RTM. (bortezomib). [0038] The invention also provides a method of inhibiting protein kinase activity of growth factor receptors which comprises administering to a mammalian species in need thereof, a therapeutically effective protein kinase inhibiting amount of a compound of formula I. [0039] Additionally, there is disclosed a method of inhibiting tyrosine kinase activity of at least one growth factor receptor such as which comprises administering to a mammalian species in need thereof, a therapeutically effective amount of a compound of formula I or II. In a preferred embodiment said growth factor receptor is selected from the group consisting of VEGFR-2 and FGFR-1. [0040] Finally, there is disclosed a method for treating a proliferative disease, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of a compound of formula I. In a preferred embodiment the proliferative disease is cancer. [0041] The following are definitions of terms that may be used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. [0042] The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms. [0043] The term "substituted alkyl" refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO.sub.2NH.sub.2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH.sub.2, substituted carbamyl e.g. CONHalkyl, CONHaryl, CONHaralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with alkyl, alkoxy, aryl or aralkyl. Continue reading about Azaindole kinase inhibitors... Full patent description for Azaindole kinase inhibitors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Azaindole kinase inhibitors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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