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(12) United States Patent (10) Patent No.: US 7,115,597 B2 Bilodeau Et Al

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(12) United States Patent (10) Patent No.: US 7,115,597 B2 Bilodeau Et Al US007 115597B2 (12) United States Patent (10) Patent No.: US 7,115,597 B2 Bilodeau et al. (45) Date of Patent: Oct. 3, 2006 (54) TYROSINE KINASE INHIBITORS J. Rak et al. Cancer Research, 55:45.75-4580, 1995. G. Gasparini and A.L. Harris, J. Clin. Oncol., 1995, 13:765-782. (75) Inventors: Mark T. Bilodeau, Lansdale, PA (US); M. Toi et al., Japan. J. Cancer Res., 1994, 85:1045-1049. George D. Hartman, Lansdale, PA A.J. Dickinson et al., Br. J. Urol., 1994, 74:762-766. (US); Jacob M. Hoffman, Jr., L.M. Ellis et al., Surgery, 1996, 120(5):871-878. Lansdale, PA (US); John T. Sisko, J.K. Williams et al., Am. J. Surg., 1994, 168:373-380. Lansdale, PA (US); Peter J. Manley, A. Amirkhosravi et al., Platelets, 10:285-292 (1999). Harleysville, PA (US); Anthony M. S.P. Gunningham, et al., Can. Research, 61.3206-3211 (2001). Smith, Green Lane, PA (US); Thomas A. Giatromanolaki et al., J. Pathol. 2001; 194: 101-108. J. Tucker, North Wales, PA (US); Michael Detmar, J. Dermatological Sci., 24 Suppl. 1, S78-S84 William C. Lumma, Jr., Helena, MT (2000). (US); Leonard Rodman, New York, Hasegawa et al., Skeletal Radiol., vol. 28, pp. 41-45, 1999. NY (US) Brockelsby et al., Laboratory Investigation 79:1101-1111 (Sep. 1999). (73) Assignee: Merck & Co., Inc., Rahway, NJ (US) Paul et al., Nature Med 7:222-227 (2001). (*) Notice: Subject to any disclaimer, the term of this Matsuyama et al., J. Neurol. Sci. 186:75-79 (2001). patent is extended or adjusted under 35 van der Flier et al., J. Infectious Diseases, 183:149-153 (2001). U.S.C. 154(b) by 215 days. Stephen K. Smith, Trends in Endocrinology & Metabolism, vol. 12, No. 4, pp. 147-151, May/Jun. 2001. (21) Appl. No.: 10/677,687 Levis et al., Blood, vol. 98, No. 3, pp. 885-887 (2001). Rajesh K. Jain, Nature Medicine, vol. 7. No. 9, pp. 987-989 (Sep. (22) Filed: Oct. 2, 2003 2001). Giulio Jori, Lasers Med. Sci., 1990; 5: 115-120. (65) Prior Publication Data Chuannong Zhou, J. Photochem. and Photobiol. 1989; 3: 299-318. Hendrich et al., Knee Surg Sports Traumatol Arthroscopy 5: 58-63 US 2004/0063720 A1 Apr. 1, 2004 (1997). Related U.S. Application Data Hall et al., Am J Hum Genet 61:785-789, 1997. Li et al., Gene Therapy, 1998; 5:1105-13. (63) Continuation of application No. 09/990,473, filed on Fathallah-Shaykh et al., J. Immunol 2000; 164:217-222. Nov. 21, 2001, now abandoned. Dougherty et al., J. Natl. Cancer Inst., 1998, 90(12): 889-905. (60) Provisional application No. 60/251,006, filed on Dec. Van Bruggen et al., J. Clin. Invest. 104:1613-1620 (1999). 4, 2000. Gerber et al., Nature Medicine, vol. 5, No. 6, pp. 623-628, 1999. David A. Greenberg, Drug News Perspect 11(5):265-270 (1998). (51) Int. Cl. Nakagawa et al., FEBS Let. 473:161-164 (2000). C07D 417/12 (2006.01) Peter Traxler, Exp. Opin. Ther. Patents 8 (12) 1599-1625(1998). A6 IK 3/427 (2006.01) Peter M. Traxler, Exp. Opin. Ther. Patents 7(6) 571-588 (1997). CO7D 241/04 (2006.01) Joseph V. Simone, Cecil Textbook of Medicine 20th Edition, vol. 1, (52) U.S. Cl. .............. 514/217.06:514/218: 514/227.8; pp. 1004-1010 (1996). 514/235.8: 514/249; 514/252.19; 514/256; 540/492; 540/575; 540/601:544/60; 54.4/121: * cited by examiner 544/122:544/328 Primary Examiner Deepak Rao (58) Field of Classification Search ................ 540/492, (74) Attorney, Agent, or Firm Dianne Brown; Mark R. 540/575, 601: 544/60, 121, 122,328; 514/217.06, Daniel 514/218, 227.8, 235.8, 249, 252.19, 256 See application file for complete search history. (57) ABSTRACT (56) References Cited FOREIGN PATENT DOCUMENTS The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduc EP 1040831 A2 4/2000 tion, compositions which contain these compounds, and WO WO95/3375O 12/1995 methods of using them to treat tyrosine kinase-dependent WO WO 99.65884 6, 1999 diseases and conditions, such as angiogenesis, cancer, tumor WO WOOOf 39101 T 2000 growth, atherosclerosis, age related macular degeneration, WO WOOOf 62778 10, 2000 diabetic retinopathy, inflammatory diseases, and the like in OTHER PUBLICATIONS mammals. Roodhooft, PubMed Abstract (Bull Soc Belge Ophthalmol. 276:83 92), 2000.* 31 Claims, No Drawings US 7,115,597 B2 1. 2 TYROSINE KNASE INHIBITORS Both receptor-type and non-receptor type tyrosine kinases are implicated in cellular signaling pathways leading to DOMESTIC PRIORITY CLAIM numerous pathogenic conditions, including cancer, psoriasis and hyperimmune responses. This continuation claims priority to application Ser. No. 5 Several receptor-type tyrosine kinases, and the growth factors that bind thereto, have been Suggested to play a role 09/990,473, filed on Nov. 21, 2001, now abandoned, which in angiogenesis, although some may promote angiogenesis claims the priority of U.S. Provisional Application No. indirectly (Mustonen and Alitalo, J. Cell Biol. 129:895–898, 60/251,006, filed on Dec. 4, 2000. 1995). One such receptor-type tyrosine kinase is fetal liver 10 kinase 1 or FLK-1. The human analog of FLK-1 is the kinase BACKGROUND OF THE INVENTION insert domain-containing receptor KDR, which is also known as vascular endothelial cell growth factor receptor 2 The present invention relates to compounds which inhibit, or VEGFR-2, since it binds VEGF with high affinity. Finally, regulate and/or modulate tyrosine kinase signal transduc the murine version of this receptor has also been called NYK tion, compositions which contain these compounds, and 15 (Oelrichs et al., Oncogene 8(1): 11–15, 1993). VEGF and methods of using them to treat tyrosine kinase-dependent KDR are a ligand-receptor pair that play an important role diseases and conditions, such as angiogenesis, cancer, tumor in the proliferation of vascular endothelial cells, and the growth, atherosclerosis, age related macular degeneration, formation and sprouting of blood vessels, termed vasculo diabetic retinopathy, inflammatory diseases, and the like in genesis and angiogenesis, respectively. mammals. Angiogenesis is characterized by excessive activity of vascular endothelial growth factor (VEGF). VEGF is actu Tyrosine kinases are a class of enzymes that catalyze the ally comprised of a family of ligands (Klagsburn and transfer of the terminal phosphate of adenosine triphosphate D'Amore, Cytokine & Growth Factor Reviews 7:259-270, to tyrosine residues in protein Substrates. Tyrosine kinases 1996). VEGF binds the high affinity membrane-spanning play critical roles in signal transduction for a number of cell 25 tyrosine kinase receptor KDR and the related fins-like functions via Substrate phosphorylation. Though the exact tyrosine kinase-1, also known as Flt-1 or vascular endothe mechanism of signal transduction is still unclear, tyrosine lial cell growth factor receptor 1 (VEGFR-1). Cell culture kinases have been shown to be important contributing and gene knockout experiments indicate that each receptor factors in cell proliferation, carcinogenesis and cell differ contributes to different aspects of angiogenesis. KDR medi entiation. 30 ates the mitogenic function of VEGF whereas Flt-1 appears Tyrosine kinases can be categorized as receptor type or to modulate non-mitogenic functions such as those associ non-receptor type. Receptor type tyrosine kinases have an ated with cellular adhesion. Inhibiting KDR thus modulates extracellular, a transmembrane, and an intracellular portion, the level of mitogenic VEGF activity. In fact, tumor growth while non-receptor type tyrosine kinases are wholly intrac has been shown to be susceptible to the antiangiogenic ellular. 35 effects of VEGF receptor antagonists. (Kim et al., Nature 362, pp. 841-844, 1993). The receptor-type tyrosine kinases are comprised of a Solid tumors can therefore be treated by tyrosine kinase large number of transmembrane receptors with diverse bio inhibitors since these tumors depend on angiogenesis for the logical activity. In fact, about twenty different subfamilies of formation of the blood vessels necessary to support their receptor-type tyrosine kinases have been identified. One 40 growth. These solid tumors include histiocytic lymphoma, tyrosine kinase subfamily, designated the HER subfamily, is cancers of the brain, genitourinary tract, lymphatic system, comprised of EGFR, HER2, HER3, and HER4. Ligands of stomach, larynx and lung, including lung adenocarcinoma this subfamily of receptors include epithileal growth factor, and Small cell lung cancer. Additional examples include TGF-C. amphiregulin, HB-EGF, betacellulin and heregulin. cancers in which overexpression or activation of Raf-acti Another Subfamily of these receptor-type tyrosine kinases is 45 Vating oncogenes (e.g., K-ras, erb-B) is observed. Such the insulin subfamily, which includes INS-R, IGF-IR, and cancers include pancreatic and breast carcinoma. Accord IR-R. The PDGF subfamily includes the PDGF-C. and B ingly, inhibitors of these tyrosine kinases are useful for the receptors, CSFIR, c-kit and FLK-II. Then there is the FLK prevention and treatment of proliferative diseases dependent family which is comprised of the kinase insert domain on these enzymes. receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver 50 The angiogenic activity of VEGF is not limited to tumors. kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (filt-1). VEGF accounts for most of the angiogenic activity produced The PDGF and FLK families are usually considered together in or near the retina in diabetic retinopathy. This vascular due to the similarities of the two groups. For a detailed growth in the retina leads to visual degeneration culminating discussion of the receptor-type tyrosine kinases, see Plow in blindness.
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