Invented by Michael Cox, Nisha Nanda, Loxo Oncology Inc
The Loxo Oncology Inc invention works as followsThe method includes administering to the subject a therapeutically effective amount of (S)?N-(5-((R)-2,5-difluorophenyl)pyrrolidin-1 yl), pyrazolo[1,5a]pyrimidin-3 yl), or a pharmaceutically acceptable salt thereof, or a combination thereof. The method includes administering to the subject a therapeutically effective amount of (S)?N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, or a combination thereof.
Background for Methods for treating pediatric cancers
The present disclosure relates to (S)?N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (Formula (I)) and to pharmaceutically acceptable salts thereof, for example the hydrogen sulfate salt, a crystalline form of the hydrogen sulfate salt, and further to liquid formulations thereof, which exhibit Trk family protein tyrosine kinase inhibition, and the use of the compound, salts, crystalline forms, and liquid formulations in the treatment of pediatric cancers.
Infantile Fibrosarcoma” (IFS) can be a rare childhood cancer that typically presents in the first 2 years of life. The surgical resection is curative, and chemotherapy can treat the gross residual disease. When recurrences do occur, the therapeutic options can be limited.
Trks are high affinity receptor tyrosine-kinases that are activated by a family of growth factors known as neurotrophins” TrkA, TrkB, and TrkC are the three members of the Trk receptor family. TrkA is activated by nerve growth factor, whereas TrkB is activated by brain-derived neurotrophic (BDNF), NT-4/5 and NT-3. TrkC can be activated with NT3. Trk’s can be found in large quantities in neuronal tissues and they are involved in maintaining, signaling, and the survival of neurons (Patapoutian A. and colleagues, Current Opinions in Neurobiology 2001, 11, 272-280).
Recent literature has shown that Trk activation, overexpression, amplification, and/or mutation are associated with cancers, including neuroblastoma. (Brodeur G. M. Nat. Rev. Cancer 2003, 3, 203-216), ovarian cancer (Davidson, B. et al., Clin. Cancer Res. 2003, 9, 2248-2259), breast cancer (Kruettgen et al., Brain Pathology 2006, 16: 304-310), prostate cancer (Dionne et al., Clin. Cancer Res. Cancer Res. (2001) Cancer Letters 169:107-114; Meyer, J. et al. Leukemia (2007), 1-10. Pierottia M. A. & Greco A. (2006) Cancer Letters: 232:90 – 98. Eric Adriaenssens E. Cancer Res (2008) 68: (2) 346-351), thyroid carcinoma (Brzezianska et al., Neuroendocrinology Letters 2007, 28(3), 221-229), lung adenocarcinoma (Perez-Pinera et al., Molecular and Cellular Biochemistry 2007, 295 (1&2), 19-26), large cell neuroendocrine tumors (Marchetti et al., Human Mutation 2008, 29(5), 609-616), and colorectal cancer (Bardelli, A., Science 2003, 300, 949). Trk inhibitors have been shown to be effective in preclinical cancer models at both stopping tumor progression and inhibiting tumor growth. Particularly, small molecule non-selective inhibitors of TrkA and TrkB were effective in stopping tumor growth as well as tumor metastasis. (2001) Cancer Letters 169:107-114; Meyer, J. et al. Leukemia, 1-10 (2007); Pierottia M. A. & Greco A. (2006) Cancer Letters: 232:90-98. Eric Adriaenssens E. Cancer Res (2008) (68: 2) 346-351). Cancer Res (2008) 68: (2) 346-351).
The Trk/neurotrophin pathways have also been shown to be effective for a variety of pre-clinical models of pain. In animal models of inflammatory pain and neuropathic symptoms, anti-NGF and TrkA antibodies, such as RN-624, have shown efficacy (Woolf C. J. et. al.). (1994) Neuroscience 62, 327-331; Zahn, P. K. et al. (2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995) Nat. Med. Ma, Q. P., and Woolf C. J. (1997) Neuroreport 8, 807-810; Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15, 355-361; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442-448). Recent literature also indicates that after inflammation, BDNF and TrkB signals are increased in the dorsal ganglion (Cho L. et. al.). Brain Research 1997, 754, 358, and a number of studies have shown that antibodies that inhibit the BDNF/TrkB signaling pathway can reduce neuronal hypersensitization, and pain associated with it (Chang Qi, L et. al. Molecular Pain 2008 4:27).
It has been demonstrated that NGF released by tumor cells or tumor-invading macrophages stimulates TrkA on peripheral nerve fibers. It was shown that using various tumor models on mice and rats, neutralizing NGF by monoclonal antibodies inhibits cancer-related pain to an extent similar or superior than the highest tolerated dosage of morphine. In addition, activation the BDNF/TrkB pathways has been implicated as a modulator in many studies of different types of pain, including inflammatory pain. 2005, 569, 685-95), and neuropathic (Thompson S. W. Proc. Natl. Acad. Sci. USA 1999, 96, 7714-18), and surgical pain. Molecular Pain 2008, 4(28), 1-6. Inhibitors of TrkA or other Trk kinases could be effective in treating chronic pain conditions.
The current treatment regimens are based on several different classes of compounds. Opioids (such as Morphin) can have several negative effects including respiratory, constipatory, and emetic. They also carry the risk of addiction. NSAIDs such as COX-1 and COX-2 have their own drawbacks. They are not effective in treating severe pain. COX-1 inhibitors can also cause mucosal ulcers. There is therefore a constant need for more effective and new treatments to relieve pain, particularly chronic pain.
Inhibition of the neurotrophin/Trk pathways has also been shown to be an effective treatment in pre-clinical models for inflammatory diseases.” Inhibition of the neurotrophin/Trk path has been implicated, for example, in preclinical lung disease models including asthma (Freund Michel, V., Frossard N., Pharmacology & Therapeutics 2008, 117(1) 52-76), and interstitial cystitis. al. The Journal of Urology, (2005) 173(3) 1016-21), ulcerative colitis, Crohn’s Disease (Di Mola F. F., et. Gut (2000) 46(5) 670-678, et. al. Archives of Dermatological Research 2006, 298(1): 31-37), Eczema and Psoriasis, (Raychaudhuri S. P. al. Journal of Investigative Dermtology (2004) 122(3) 812-819).
The neurotrophin/Trk path, specifically BDNF/TrkB has been implicated in the etiology for neurodegenerative disorders including multiple sclerosis (Sohrabji Farida, Lewis Danielle K., Frontiers in Neuroendocrinology, 2006, 27(4), 404-414). The neutrophin/Trk pathway may be useful in treating these diseases and others.
The TrkA receptor may also be crucial to the disease process of Trypanosoma cruzi infection in humans (de Melo Jorge et al. Cell Host & Microbe (2007) 1(4): 251-261. TrkA inhibitors may be useful in treating Chagas and other protozoan infections.
Trk inhibiters may also be used to treat diseases related to an imbalance in the regulation of bone remodelling, such as osteoporosis and rheumatoid arthritis, or bone metastases. Bone metastases can be a common complication in cancer patients. They occur in as many as 70 percent of those with advanced prostate or breast cancer. In addition, they are found in 15-30 percent of those with cancers of the uterus or rectum. Osteolytic metastatic lesions can lead to severe pain, pathological fractures, hypercalcemia that is life-threatening, spinal cord compression and other nerve-compression disorders. Bone metastasis can be a costly and serious cancer complication. Agents that induce the apoptosis in osteoblasts are highly beneficial. In mouse models of fractured bone, TrkA- and TrkC-receptors were expressed in the bone-forming area (K. Asaumi et. al., Bone 2000 26 (6), 625-633). NGF localization was also observed in nearly all bone-forming cells (K. Asaumi et. al.). Recent studies have shown that a pan Trk inhibitor inhibits tyrosine-mediated signaling triggered by neurotrophins binding all three Trk receptors on human hFOB osteblasts (J. Pinski et. al., 2002 62, 986-989). These data support the rationale of using Trk inhibitors to treat bone remodeling diseases such as metastases of cancer in patients.
Expert opinion) “Several classes small molecule inhibitors Trk kinases are known to be useful in treating cancer or pain (Expert Opinion). Ther. Patents (2009), 19 (3 )).
The International Patent Application Publications (WO 2006/115452 WO 06/087538) describe several classes small molecules that are said to be Trk kinase inhibitors which could be used for treating cancer or pain.
Pyrazolo[1,5-a]pyrimidine compounds are known. For example, International Patent Application Publication WO 2008/037477 discloses pyrazolo[1,5-a]pyrimidine compounds bearing an alkyl, aryl or heterocyclic group at the 3-position. These compounds are claimed to be PI3K or mTOR Lipidkinase Inhibitors.
PCT Patent Publication No. WO 2008/058126 discloses pyrazolo[1,5-a]pyrimidine compounds bearing a phenyl group at the 3-position. These compounds are claimed to be Pim kinase inhibitors.
U.S. Patent Publication No. 2006/0094699 discloses pyrazolo[1,5-a]pyrimidine compounds bearing a ?C(?O)NH-phenyl, ?C(?O)(4-methylpiperidinyl) or ?C(?O)NMe(CH2-trimethylpyrazolyl) group at the 3-position for use in combination therapy with a glucocorticoid receptor agonist.
PCT Patent Publication Nos. “PCT Patent Publication Nos.
WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)?N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. The hydrogen sulfate described in WO 2010/048314 is not disclosed when prepared using the Example 14A method. In particular, WO2010/048314 doesn’t disclose the crystalline form (IHS) described below.
All documents, such as scientific articles, publications, applications and patents, etc., referred to in the disclosure are hereby included by reference.
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