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(12) United States Patent (10) Patent No.: US 9,676,746 B2 Decrescenzo Et Al

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USOO9676746B2 (12) United States Patent (10) Patent No.: US 9,676,746 B2 DeCrescenzo et al. (45) Date of Patent: Jun. 13, 2017 (54) CRYSTALLINE FORMS OF CHCLNO, USPC .......................................................... 514/343 See application file for complete search history. (71) Applicants: BIOMED VALLEY DISCOVERIES, INC., Kansas City, MO (US); (56) References Cited VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US) U.S. PATENT DOCUMENTS 7,354,939 B2 4/2008 Martinez-Botella et al. (72) Inventors: Gary DeCrescenzo, Parkville, MO 2003/0040536 A1 2/2003 Hale et al. (US); Dean Welsch, Parkville, MO 2004.0029857 A1 2/2004 Hale et al. (US); Petinka I. Vlahova, West 2015,005.1209 A1 2/2015 Bock et al. Lafayette, IN (US); Stephan X. M. Boerrigter, West Lafayette, IN (US); OTHER PUBLICATIONS Alexander Aronov, Newton, MA (US); Ali Keshavarz-Shokri, San Diego, CA Chemietek "Certificate of Analysis: Ulixertinib (Hydrochloride)” (US); Alexander N. Scangas, Copyright 2014. Retrieved from the Internet retrieved on Sep. 9, Wilmington, MA (US); Kathy 2016 <URL: http://www.chemietek.com/ProductFiles/Coal Ulixertinib.%20(HC1%20salt),%20Lot%2001.%20Certificate Stavropoulos, Quincy, MA (US); %20of%20Analysis.pdf>. Benjamin Littler, Carlsbad, CA (US); International Search Report for PCT/US2016/015829 mailed Apr. 7, Irina Nikolaevna Kadiyala, Newton, 2016. MA (US); Rossitza Gueorguieva Kohno M and Pouyssegur J. (2006) Targeting the ERK signaling Alargova, Brighton, MA (US) pathway in cancer therapy. Ann Med 38: 200-211. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson O (2006) (73) Assignees: BioMed Valley Discoveries, Inc., Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science. J Pharm Pharmaceut Sci 9(3):317-326. Kansas City, MO (US); Vertex Written Opinion of the International Searching Authority for PCT/ Pharmaceuticals Incorporated, US2016/015829 mailed Apr. 7, 2016. Boston, MA (US) Primary Examiner — Yevegeny Valenrod (*) Notice: Subject to any disclaimer, the term of this (74) Attorney, Agent, or Firm — Bryan Cave LLP patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (57) ABSTRACT (21) Appl. No.: 15/011,377 The present invention provides crystalline forms of a com pound of formula (I): (22) Filed: Jan. 29, 2016 (65) Prior Publication Data US 2016/0221987 A1 Aug. 4, 2016 Related U.S. Application Data (60) Provisional application No. 62/110,449, filed on Jan. 30, 2015. C. (51) Int. Cl. CO7D 40/04 (2006.01) A6 IK 45/06 (2006.01) A6 IK 3/4439 (2006.01) Also provided are pharmaceutical compositions that include (52) U.S. Cl. the provided crystalline forms and methods of using the CPC ........ C07D 401/04 (2013.01); A6IK3I/4439 provided crystalline forms and pharmaceutical compositions (2013.01); A61K 45/06 (2013.01) for the treatment of cancer. (58) Field of Classification Search CPC ... CO7D 401/04; A61K 31/4439; A61K 45/06 82 Claims, 14 Drawing Sheets U.S. Patent Jun. 13, 2017 Sheet 1 of 14 US 9,676,746 B2 8 s ..-assis-- - ^ 3r : X S r sy 3 s (syriano) sistiau U.S. Patent Jun. 13, 2017 Sheet 2 of 14 US 9,676,746 B2 & s s S. s S.S s U.S. Patent Jun. 13, 2017 Sheet 3 of 14 US 9,676,746 B2 b i s b b b b & a : b s SSSssssssss S. Ex k w8. & U.S. Patent Jun. 13, 2017 Sheet 4 of 14 US 9,676,746 B2 was 3.xxxxxxxxx xxxx was SSSSSSSSSSSSSSS Sassassasssssssssssssssssssssssss -Saxxx xxxx xxxxx xxxxxxxxxx-xxxxxx --xxxxx xxxx-xx-xxx-xxxxxxxxxxx-xxxxxxxx xxx; RSSSS *Sasas: SSSSS &Swississssssssssssssssssssssss: Sassasssssss:::::::::::::::::: xxxssssssssssssssssssssssssssssssss-Xxxxxx...SSS sw8xx s was: i S www.www.swisssssssssssssssssssssssssssssssssssssssssssssssssssssss SSSSSSSSSSSSSSSSS: s U.S. Patent Jun. 13, 2017 Sheet 6 of 14 US 9,676,746 B2 &x Ss eyes sww R&eeeeeeee w & | W S. S. S S & S. is is 888 & 8 U.S. Patent Jun. 13, 2017 Sheet 9 of 14 US 9,676,746 B2 -Y^mss U.S. Patent Jun. 13, 2017 Sheet 10 of 14 US 9,676,746 B2 s8. R Sssssssssssssssssssaxxx xxxxaaaaaaaaaaaaaaaaaassssssssssss assssssssssssssssssssssss: s:SSSSSSSSSSSSSSSSSS333Sssssssssssss Y--------------Saxxx-x-xx-xx-xxx-xx-x-x-xx-xx-x- s sixx xxx; U.S. Patent Jun. 13, 2017 Sheet 12 of 14 US 9,676,746 B2 M * Ow & xxxxx^^^ &r -Y & ^ r s Y x S. R & S. U.S. Patent Jun. 13, 2017 Sheet 13 of 14 US 9,676,746 B2 --******… ~~~~…,„~~~~~~*~~~~~~~~~~….... sh: k, x retressertarresearrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrre S. s U.S. Patent Jun. 13, 2017 Sheet 14 of 14 US 9,676,746 B2 ^ aaaaaaaaaaaaaaaa. ------ sistssixxxesssssssssssssssssssssssssssssssssssssssssss 3. US 9,676,746 B2 1. 2 CRYSTALLINE FORMS OF CHCL-NO, boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide can be prepared which exhibit improved properties, e.g. Surpris CROSS-REFERENCE TO RELATED ingly improved stability and improved solubility character APPLICATIONS istics. Thus, the present invention provides crystalline 4-(5- This patent application claims the benefit of U.S. Provi Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car sional Patent Application No. 62/110,449, filed Jan. 30. boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide. 2015, which is incorporated by reference herein in its entirety. The present invention also provides crystalline free base 10 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- FIELD OF THE INVENTION carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide. The present invention also provides a crystalline free base The present invention relates to crystalline forms of of a compound of formula: 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide, 15 which is useful as an inhibitor of ERK protein kinase. BACKGROUND OF THE INVENTION Mitogen-activated protein kinase (MAPK) pathways mediate signals which control diverse cellular processes including growth, differentiation, migration, proliferation C and apoptosis. One MAPK pathway, the extracellular signal regulated kinase (ERK) signaling pathway, is often found to be up-regulated in tumors. Pathway members, therefore, 25 represent attractive blockade targets in the development of cancer therapies (Kohno and Pouyssegur, 2006). For example, U.S. Pat. No. 7,354,939 B2 discloses, inter alia, having an X-ray powder diffraction (XRPD) pattern com compounds effective as inhibitors of ERK protein kinase. prising a characteristic peak at about 19.5° 20. One of these compounds, 4-(5-Chloro-2-isopropylamin 30 The present invention also provides a crystalline free base opyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chloro of a compound of formula: phenyl)-2-hydroxyethylamide, is a compound according to formula (I): 35 40 C C. 45 having an XRPD pattern comprising characteristic peaks at about 9.1 and 19.5° 20. The present invention also provides a crystalline free base Pharmaceutical compositions are often formulated with a of a compound of formula: crystalline solid of the active pharmaceutical ingredient 50 (API). The specific crystalline form of the API can have significant effects on properties such as stability and solu bility/bioavailability. Instability and solubility characteris tics can limit the ability to formulate a composition with an adequate shelf life or to effectively deliver a desired amount 55 of a drug over a given time frame (Peterson et al., 2006). There exists an unmet need for crystalline forms of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- C carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide which exhibit improved properties for formulation of phar 60 maceutical compositions. The present application is directed to meeting this and other needs. SUMMARY OF THE INVENTION having an XRPD pattern comprising characteristic peaks at 65 about 9.1, 15.4, 19.5 and 21.4° 20. It has been discovered that crystalline forms of 4-(5- The present invention also provides a crystalline free base Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car of a compound of formula: US 9,676,746 B2 C having one or more XRPD 20-reflections () selected from having an XRPD pattern comprising characteristic peaks at the group consisting of about 9.1, 12.5, 15.2, 15.4, 19.2, about 6.7 and 11.0° 20. 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 24.3. The present invention also provides a crystalline hydro The present invention also provides a crystalline free base chloride salt of a compound of formula: of a compound of formula: 25 C C 30 having an XRPD pattern comprising characteristic peaks at having an XRPD pattern substantially as shown in FIG. 1. about 6.7, 11.0, 17.6 and 19.9° 20. The present invention also provides pharmaceutical com The present invention also provides a crystalline hydro positions comprising any of the crystalline compounds of chloride salt of a compound of formula: the present invention. 35 The present invention also provides a method of treating a cancer in a Subject in need thereof comprising adminis tering to the subject an effective amount of any of the crystalline compounds of the present invention. The present invention also provides a method of treating 40 a cancer in a Subject in need thereof comprising adminis tering to the subject an effective amount of any of the pharmaceutical compositions of the present invention. The present invention also provides crystalline 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car 45 boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide mono HC1. The present invention also provides a crystalline hydro having one or more XRPD 20-reflections () selected from chloride salt of a compound of formula: the group consisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2. 50 16.5, 17.6, 17.9, 18.4, 18.7, 19.6, 19.9, and 20.4.
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    International Journal of Molecular Sciences Review Management of Brain and Leptomeningeal Metastases from Breast Cancer Alessia Pellerino 1,* , Valeria Internò 2 , Francesca Mo 1, Federica Franchino 1, Riccardo Soffietti 1 and Roberta Rudà 1,3 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (F.M.); [email protected] (F.F.); riccardo.soffi[email protected] (R.S.); [email protected] (R.R.) 2 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; [email protected] 3 Department of Neurology, Castelfranco Veneto and Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-6334904 Received: 11 September 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups.
  • New Contributions in Undergraduate Research

    New Contributions in Undergraduate Research

    PSU McNair Scholars Online Journal Volume 11 Issue 1 Without Borders: Original Contributions Article 6 in Undergraduate Research 2017 Wings Outstretched: New Contributions in Undergraduate Research Follow this and additional works at: https://pdxscholar.library.pdx.edu/mcnair Let us know how access to this document benefits ou.y Recommended Citation (2017) "Wings Outstretched: New Contributions in Undergraduate Research," PSU McNair Scholars Online Journal: Vol. 11: Iss. 1, Article 6. https://doi.org/10.15760/mcnair.2017.01 This open access Full Issue is distributed under the terms of the Creative Commons Attribution-NonCommercial- ShareAlike 4.0 International License (CC BY-NC-SA 4.0). All documents in PDXScholar should meet accessibility standards. If we can make this document more accessible to you, contact our team. Portland State University McNair Research Journal 2017 Without Borders: Original Contributions in Undergraduate Research 2017 Ronald E. McNair Scholars Journal Portland State University 1 About the Program The Portland State University (PSU) Ronald E. McNair Scholars Program at Portland State University works with motivated and talented undergraduates who want to pursue PhDs. It introduces juniors and seniors who are first-generation and low income, and/or members of under-represented groups to academic research and to effective strategies for getting into and graduating from PhD programs. The McNair Scholars Program has academic-year activities and a full-time summer research internship. Scholars take academic and skills-building seminars and workshops during the year, and each scholar works closely with a faculty mentor on original research in the summer. Scholars present their research findings at the McNair Summer Symposium and at other conferences, and are encouraged to publish their papers in the McNair Journal and other scholarly publications.
  • Biological Heterogeneity of Chondrosarcoma: from (Epi) Genetics Through Stemness and Deregulated Signaling to Immunophenotype

    Biological Heterogeneity of Chondrosarcoma: from (Epi) Genetics Through Stemness and Deregulated Signaling to Immunophenotype

    cancers Review Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype Agnieszka Zaj ˛ac 1 , Sylwia K. Król 2 , Piotr Rutkowski 1 and Anna M. Czarnecka 1,3,* 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] (A.Z.); [email protected] (P.R.) 2 Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 3 Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-176 Warsaw, Poland * Correspondence: [email protected] Simple Summary: Chondrosarcoma (ChS) is the second most frequently diagnosed malignant bone tumor of cartilaginous origin and is generally resistant to standard treatment options. In this paper, we aim to review the current state of the knowledge regarding ChS. We discuss the genetic, epigenetic, and molecular abnormalities underlying its substantial biological and clinical heterogeneity. This review summarizes the critical genetic and molecular drivers of ChS development and progression, contributing to its radio- and chemotherapy resistance. We describe genomic aberrations and point mutations, as well as epigenetic modifications and deregulated signal transduction pathways. We Citation: Zaj ˛ac,A.; Król, S.K.; provide an insight into the stem-like characteristics and immunophenotype of ChS. The paper also Rutkowski, P.; Czarnecka, A.M. outlines potential diagnostic and prognostic biomarkers of ChS and recently identified novel targets Biological Heterogeneity of for future pharmacological interventions in patients. Chondrosarcoma: From (Epi) Genetics through Stemness and Abstract: Deregulated Signaling to Chondrosarcoma (ChS) is a primary malignant bone tumor.