DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 9,670,205 B2 Aktoudianakis Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 9,670,205 B2 Aktoudianakis Et Al USOO9670205B2 (12) United States Patent (10) Patent No.: US 9,670,205 B2 Aktoudianakis et al. (45) Date of Patent: Jun. 6, 2017 (54) TOLL LIKE RECEPTOR MODULATOR FOREIGN PATENT DOCUMENTS COMPOUNDS EP 042593 A1 12, 1981 EP O322133 A1 6, 1989 (71) Applicant: Gilead Sciences, Inc., Foster City, CA EP 404355 A1 12, 1990 (US) JP 2000038350 A 2, 2000 JP 2000053.653. A 2, 2000 JP 2000053654 A 2, 2000 (72) Inventors: Evangelos Aktoudianakis, Redwood WO WO-9307124 A1 4f1993 City, CA (US); Gregory Chin, San WO WO-9427439 A1 12, 1994 Francisco, CA (US); Richard L. WO WO-0121619 A1 3, 2001 Mackman, Millbrae, CA (US); Samuel WO WO-03001887 A2 1, 2003 WO WO-2006050843 A1 5, 2006 E. Metobo, Newark, CA (US); Michael WO WO-2006069805 A2 T 2006 R. Mish, Foster City, CA (US); WO WO-2006135993 A1 12/2006 Hyung-jung Pyun, Fremont, CA (US); WO WO-2007093901 A1 8, 2007 Jeff Zablocki, Los Altos, CA (US) WO WO-2008OO97O6 A1 1, 2008 WO WO-2008O3O455 A2 3, 2008 WO WO-2008077649 A1 T 2008 (73) Assignee: GILEAD SCIENCES, INC., Foster WO WO-2008077651 A1 T 2008 City, CA (US) WO WO-2008154221 A2 12/2008 WO WO-2009003669 A2 1, 2009 (*) Notice: Subject to any disclaimer, the term of this WO WO-201OOO2998 A1 1, 2010 patent is extended or adjusted under 35 WO WO-2010O42489 A2 4/2010 WO WO-2O10046639 A1 4/2010 U.S.C. 154(b) by 0 days. WO WO-2010092340 A1 8, 2010 WO WO-2011057148 A1 5, 2011 (21) Appl. No.: 15/059,070 WO WO-2O11072275 A2 6, 2011 WO WO-20110976O7 A1 8, 2011 (22) Filed: Mar. 2, 2016 WO WO-2011 135259 A1 11/2011 WO WO-2012O58601 A1 5, 2012 (65) Prior Publication Data WO WO-2012.136834 A1 10, 2012 WO WO-2012.156498 A1 11 2012 US 2016/0289229 A1 Oct. 6, 2016 WO WO-2013060881 A1 5, 2013 WO WO-2013090840 A1 6, 2013 (Continued) Related U.S. Application Data (60) Provisional application No. 62/250,403, filed on Nov. OTHER PUBLICATIONS 3, 2015, provisional application No. 62/128.397, filed Bigorgne et al (2010) “TLRs inHepatic Cellular Crosstalk” Gas on Mar. 4, 2015. troenterology Research and Practice, Article ID 618260 pp. 1-7. Cervantes, J. et al.(2012) “TLR8: the forgotten relatuve (51) Int. Cl. revindicated” Cellular & Molecular Immunology 9:434-438. CO7D 47L/04 (2006.01) Colonna, M. et al (2004) “Plasmacytoid dendritic cells in immu (52) U.S. Cl. nity' Nature Immunology 5(12)0:1219-1226. CPC .................................. C07D 471/04 (2013.01) O'Neill, L. et al (2013) “The history of Toll-like receptors— (58) Field of Classification Search redefining innate immunity”. Nature Reviews/immunology 13:453 CPC .................................................... CO7D 471/04 460. See application file for complete search history. Partial International Search Report for PCT/US2016/020499 mailed May 3, 2016. Chapman, N. et al (1947) “Synthethic Antimalarials. Part XVI. (56) References Cited 4-Dialkylaminoalkylaminoquinazolines. Variation of Substituents U.S. PATENT DOCUMENTS in the 6-and 7-Positions” Journal of the Chemical Society 890-899. Examination Report No. 1 for Australian Patent No. 2016216673 4,608,383 A 8, 1986 Wiedemann et al. dated Sep. 5, 2016. 5,064,833. A 11/1991 Ife et al. International Search Report for PCT/US2016/020499 dated Jul. 13, 8,143,394 B2 3/2012 Watkins et al. 2019. 8,232,278 B2 7/2012 De Jonghe et al. 8,367,670 B2 2/2013 Desai et al. (Continued) 8,536,187 B2 9/2013 Canales et al. 8,637,531 B2 1/2014 Bondy et al. Primary Examiner — Timothy Thomas 8,729,089 B2 5/2014 Bondy et al. (74) Attorney, Agent, or Firm — Timothy A. Marquart 8,901,133 B2 12/2014 Ren et al. 8,916,575 B2 * 12/2014 McGowan ........... CO7D 239,95 (57) ABSTRACT 514,266.1 8,969,363 B2 3/2015 Castro et al. The present disclosure relates generally to toll like receptor 2008.0004285 A1 1/2008 De Jonghe et al. modulator compounds, such as diamino pyrido3.2 Dipy 2008. O182870 A1 7/2008 Bondy et al. rimidine compounds and pharmaceutical compositions 2009,003.6430 A1 2/2009 De Jonghe et al. 2012/O122838 A1 5, 2012 Ren et al. which, among other things, modulate toll-like receptors (e.g. 2012fO238587 A1 9, 2012 Lee et al. TLR-8), and methods of making and using them. 2013, OO29982 A1 1/2013 Castro et al. 2013,0109693 A1 5, 2013 Routier et al. 16 Claims, No Drawings US 9,670.205 B2 Page 2 (56) References Cited FOREIGN PATENT DOCUMENTS WO WO-20131-17615 A1 8, 2013 WO WO-2013174947 A1 11 2013 WO WO-2014023813 A1 2, 2014 WO WO-2O14056.953 A1 4/2014 WO WO-2014O76221 A1 5, 2014 WO WO-2014 120995 A2 8, 2014 WO WO-2014 128189 A1 8, 2014 WO WO-2015O14815 A1 2, 2015 WO WO-2015 191752 A1 12/2015 OTHER PUBLICATIONS Kaczanoska, S. et al. (2013) “TLR agonists: our best frenemy in cancer immunotherapy” Journal of Leukocyte Biology 93(6):847 863. Search Report for Korean Patent Application 10-2016-7023289 dated Aug. 25, 2016 with English translation. Xagorari (2008) "Toll-Like Receptors and Viruses: Induction of Innate Antiviral Immune Responses” The Open Microbiology Jour nal 2:49-59. Yin, P. et al. (2012) "Synthesis of 2,4-Diaminoquinazolines and Tricyclis Quinazolines by Cascade Reductive Cyclization of Methyl N-Cyano-2-notrobenzimidates.” The Journal of Organic Chemistry T7:2649-2658. Examination Report dated Nov. 14, 2016 for AU Patent Application No. 2016216673. Examination Report dated Nov. 29, 2016 or EP Patent Application No. 1671 1723.3. Notice of Preliminary Rejection dated Oct. 14, 2016 for Korean Patent Application No. 10-2016-7023289. Office Action dated Dec. 27, 2016 for U.S. Appl. No. 15/264,401. * cited by examiner US 9,670,205 B2 1. 2 TOLL LIKE RECEPTOR MODULATOR COMPOUNDS R (J) YNH CROSS REFERENCE TO RELATED R X APPLICATIONS n NN This application claims priority to U.S. Provisional Appli R2 21 as als NH2 cation No. 62/128,397, filed Mar. 4, 2015, and 62/250,403, filed Nov. 3, 2015, both of which are incorporated herein in 10 R3 their entireties for all purposes. FIELD 15 or a pharmaceutically acceptable salt thereof, wherein: This application relates generally to toll like receptor X is N or CR; modulator compounds, including diamino pyrido3.2 Dipy R" is selected from the group consisting of hydrogen, rimidine compounds, and pharmaceutical compositions halogen, Calkyl, CN, NR'R'', S(O).R", and which, among other things, modulate toll-like receptors (e.g. OR", wherein Calkyl is optionally substituted with 1 TLR-8), and methods of making and using them. to 5 R' groups; R is selected from the group consisting of hydrogen, BACKGROUND halogen, Calkyl, CN, NR'R'', S(O).R" and OR", wherein Calkyl is optionally substituted with 1 The toll-like receptor (TLR) family plays a fundamental 25 to 5 R' groups; role in pathogen recognition and activation of innate immu R is selected from the group consisting of hydrogen, nity. Toll-like receptor 8 (TLR-8) is predominantly halogen, Calkyl, CN, NR'R''. —S(O), R', and expressed by myeloid immune cells and activation of this OR", wherein Calkyl is optionally substituted with 1 receptor stimulates a broad immunological response. Ago 30 to 5 R' groups; nists of TLR-8 activate myeloid dendritic cells, monocytes, monocyte-derived dendridic cells and Kupffer cells leading R" is C. alkyl which is optionally substituted with 1 to to the production of proinflammatory cytokines and 5 substituents independently selected from halogen, chemokines, such as interleukin-18 (IL-18), interleukin-12 OR, NR'R'', CN, C(O)R, C(O)OR", (IL-12), tumor necrosis factor-alpha (TNF-C.), and inter 35 C(O)NR'R'', OC(O)NR'R'', NRC(O)R’, feron-gamma (IFN-Y). Such agonists also promote the NRC(O)NR', NRC(O)OR', SR', S(O), increased expression of co-stimulatory molecules Such as R", -S(O)NR'R'', -NR'S(O).R, Chaloalkyl, CD8 cells, major histocompatibility complex molecules C-cycloalkyl, 3 to 6 membered heterocyclyl wherein (MAIT, NK cells), and chemokine receptors. the 3 to 6 membered heterocyclyl has 1 to 3 heteroa 40 toms selected from oxygen, nitrogen, and Sulfur, Co Collectively, activation of these innate and adaptive aryl, and 5 to 10 membered heteroaryl wherein the 5 to immune responses induces an immune response and pro 10 membered heteroaryl has 1 to 3 heteroatoms vides a therapeutic benefit in various conditions involving Selected from oxygen, nitrogen, and Sulfur, autoimmunity, inflammation, allergy, asthma, graft rejec tion, graft versus host disease (GvHD), infection, cancer, wherein each Cecycloalkyl, 3 to 6 membered heterocy and immunodeficiency. For example, with respect to hepa 45 clyl, Co aryl, and 5 to 10 membered heteroaryl is titis B, activation of TLR8 on professional antigen present optionally substituted with 1 to 5 R' groups: ing cells (pAPCs) and other intrahepatic immune cells is R" is selected from hydrogen, halogen, Calkyl, CN, associated with induction of IL-12 and proinflammatory - NR'R'', -S(O) R', and OR", wherein Calkyl is cytokines, which is expected to augment HBV-specific T cell 50 optionally substituted with 1 to 5 R' groups responses, activate intrahepatic NK cells and drive recon each R" is independently selected from the group con stitution of antiviral immunity. See e.g. Wille-Reece, U. et sisting of halogen, Chaloalkyl, CN, NR'R'', al.
Load more

Recommended publications
  • An Overview of the Role of Hdacs in Cancer Immunotherapy
    International Journal of Molecular Sciences Review Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy Debarati Banik, Sara Moufarrij and Alejandro Villagra * Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, 800 22nd St NW, Suite 8880, Washington, DC 20052, USA; [email protected] (D.B.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: +(202)-994-9547 Received: 22 March 2019; Accepted: 28 April 2019; Published: 7 May 2019 Abstract: Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration.
    [Show full text]
  • SPECIALTY MEDICATIONS Available Through Accredo Health Group, Inc., Medco’S Specialty Pharmacy Call Toll-Free (800) 803-2523, 8:00 A.M
    SPECIALTY MEDICATIONS available through Accredo Health Group, Inc., Medco’s specialty pharmacy Call toll-free (800) 803-2523, 8:00 a.m. to 8:00 p.m., eastern time, Monday through Friday, to confirm that your medication is covered. Effective as of July 1, 2011 Abraxane® (paclitaxel protein-bound particles) Berinert® (C 1 esterase inhibitor [human])* (PA) (QD) Actemra ™ (tocilizumab) (PA) Betaseron® (interferon beta-1b) (PA) Actimmune® (interferon gamma-1b) (PA) Botox® (botulinum toxin type A) (PA) Adagen® (pegademase bovine) Carbaglu ™ (carglumic acid) Adcirca® (tadalafil) (ST) (QD) Carimune® NF (immune globulin intravenous [human]) (PA) Advate® (antihemophilic factor [recombinant]) (CPA) Cerezyme® (imiglucerase) (CPA) (ST) Afinitor® (everolimus) (PA) (QD) Cimzia® (certolizumab pegol) (ST) Aldurazyme® (laronidase) (CPA) Copaxone® (glatiramer acetate) (PA) Alphanate® (antihemophilic factor [human]) (CPA) Copegus® (ribavirin) (ST) AlphaNine® SD (coagulation factor IX [human]) (CPA) Corifact® (factor XIII [human]) (CPA) Amevive® (alefacept) (PA) Cystadane® (betaine) Ampyra ™ (dalfampridine) (PA) CytoGam® (cytomegalovirus immune globulin Apokyn® (apomorphine hydrochloride) (PA) (QD) intravenous [human])* (CPA) Aralast® (alpha[1]-proteinase inhibitor [human]) Cytovene® IV (ganciclovir sodium)* Aranesp® (darbepoetin alfa) (PA) Dacogen® (decitabine) Arcalyst® (rilonacept) (PA) (QD) Dysport® (abobotulinumtoxinA) (PA) Arixtra® (fondaparinux sodium)* Egrifta ™ (tesamorelin) (PA) Arranon® (nelarabine) Elaprase® (idursulfase) (CPA) Arzerra® (ofatumumab)
    [Show full text]
  • Cyclacel Announces Grants of New U.S. & European Patents
    February 12, 2013 Cyclacel Announces Grants of New U.S. & European Patents Covering Sapacitabine Used in Combination With HDAC Inhibitors Granted Patents Provide Exclusivity for Potential Uses of Sapacitabine in Hematological Malignancies and Solid Tumors BERKELEY HEIGHTS, N.J., Feb. 12, 2013 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) (Cyclacel or the Company), a biopharmaceutical company developing oral therapies that target the various phases of cell cycle control for the treatment of cancer and other serious disorders, today announced the issuance of U.S. Patent No. US 8,349,792 ('792) and European Patent No 2,101,790 ('790). Both patents include claims to combination treatment of sapacitabine, the Company's lead product candidate, with HDAC (histone deacetylase) inhibitors. The patents provide exclusivity until June 2029 and December 2027 respectively. "The grants of the '792 and '790 patents are important enhancements of sapacitabine's intellectual property estate. They supplement sapacitabine's existing composition of matter, dosing regimen and combination treatment patent protection and support US and EU market exclusivity toward the end of the next decade," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "We are pursuing a broad intellectual property strategy providing us with a strong foundation to achieve our clinical and commercial objectives for sapacitabine and our other assets. As we continue to enroll SEAMLESS, our pivotal Phase 3 trial of sapacitabine as front-line treatment in elderly patients with acute myeloid leukemia (AML), we look forward to providing additional updates for sapacitabine this year, including Phase 2 data in myelodysplastic syndromes (MDS), AML preceded by MDS, and solid tumors." The two patents include claims to combinations of sapacitabine and HDAC inhibitors, pharmaceutical compositions comprising sapacitabine and HDAC inhibitors, and methods of treatment using such compositions of proliferative disorders including leukemias, lymphomas, and lung cancer.
    [Show full text]
  • What Lessons Can We Learn from 20 Years of Chemokine T D Di ? Receptor
    What lessons can we learn from 20 years of chemokine receptdtor drug discovery? John G. Cumming, PhD 5th RSC / SCI symposium on GPCRs in Medicinal Chemistry 15th-17th September 2014, Actelion, Allschwil, Basel, Switzerland Outline Background: chemokines and their receptors Chemokine receptor drug discovery and development Emerging opportunities for chemokine drug discovery Conclusions and learning Chemokines and chemokine receptors CXC(α) • Chemokines (chemoattractant cytokines) are 70-120 aa proteins • 44 chemokines in 4 major families and 22 chemokine receptors in human genome • ‘Cell positioning system’ in the body • Many receptors bind multiple ligands • Many ligands bind multiple receptors Chemotaxis Human monocytes + CCL2 (red) Volpe et al. PLoS ONE 2012, 7(5), e37208 CCR2 antagonists inhibit chemotaxis and infiltration Vasculature CCL2 release Spinal or Peripheral Tissue Recruited monocyte Site of CCL2 release CCR2 antagonists inhibit chemotaxis and infiltration CCR2 antagonist Circulating monocyte CCL2 release CCL2 release from peripheral injury site or central PAF terminals Role of chemokine system in pathophysiology • Potential role in inflammatory and autoimmune diseases: Multiple sclerosis, Rheumatoid arthritis, COPD, allergic asthma, IBD, psoriasis - Expression levels of chemokines and receptors in relevant tissues and organs of patients and animal disease models - Mouse knockout ppyphenotype in disease models • Established role in HIV infection Katschke et al., 2001 Arthritis Rheum, 44, 1022 - CCR5 and CXCR4 act as HIV-1
    [Show full text]
  • Horizon Scanning Status Report, Volume 2
    PCORI Health Care Horizon Scanning System Volume 2, Issue 3 Horizon Scanning Status Report September 2020 Prepared for: Patient-Centered Outcomes Research Institute 1828 L St., NW, Suite 900 Washington, DC 20036 Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12 Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462 Investigators: Randy Hulshizer, MA, MS Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, PA-C Marcus Lynch, PhD, MBA Misha Mehta, MS Prital Patel, MPH Brian Wilkinson, MA Donna Beales, MLIS Jennifer De Lurio, MS Eloise DeHaan, BS Eileen Erinoff, MSLIS Cassia Hulshizer, AS Madison Kimball, MS Maria Middleton, MPH Diane Robertson, BA Melinda Rossi, BA Kelley Tipton, MPH Rosemary Walker, MLIS Andrew Furman, MD, MMM, FACEP Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the Horizon Scanning System has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.
    [Show full text]
  • Histone Deacetylase Inhibitors: a Prospect in Drug Discovery Histon Deasetilaz İnhibitörleri: İlaç Keşfinde Bir Aday
    Turk J Pharm Sci 2019;16(1):101-114 DOI: 10.4274/tjps.75047 REVIEW Histone Deacetylase Inhibitors: A Prospect in Drug Discovery Histon Deasetilaz İnhibitörleri: İlaç Keşfinde Bir Aday Rakesh YADAV*, Pooja MISHRA, Divya YADAV Banasthali University, Faculty of Pharmacy, Department of Pharmacy, Banasthali, India ABSTRACT Cancer is a provocative issue across the globe and treatment of uncontrolled cell growth follows a deep investigation in the field of drug discovery. Therefore, there is a crucial requirement for discovering an ingenious medicinally active agent that can amend idle drug targets. Increasing pragmatic evidence implies that histone deacetylases (HDACs) are trapped during cancer progression, which increases deacetylation and triggers changes in malignancy. They provide a ground-breaking scaffold and an attainable key for investigating chemical entity pertinent to HDAC biology as a therapeutic target in the drug discovery context. Due to gene expression, an impending requirement to prudently transfer cytotoxicity to cancerous cells, HDAC inhibitors may be developed as anticancer agents. The present review focuses on the basics of HDAC enzymes, their inhibitors, and therapeutic outcomes. Key words: Histone deacetylase inhibitors, apoptosis, multitherapeutic approach, cancer ÖZ Kanser tedavisi tüm toplum için büyük bir kışkırtıcıdır ve ilaç keşfi alanında bir araştırma hattını izlemektedir. Bu nedenle, işlemeyen ilaç hedeflerini iyileştirme yeterliliğine sahip, tıbbi aktif bir ajan keşfetmek için hayati bir gereklilik vardır. Artan pragmatik kanıtlar, histon deasetilazların (HDAC) kanserin ilerleme aşamasında deasetilasyonu arttırarak ve malignite değişikliklerini tetikleyerek kapana kısıldığını ifade etmektedir. HDAC inhibitörleri, ilaç keşfi bağlamında terapötik bir hedef olarak HDAC biyolojisiyle ilgili kimyasal varlığı araştırmak için, çığır açıcı iskele ve ulaşılabilir bir anahtar sağlarlar.
    [Show full text]
  • Supplementary Material Table of Contents
    Supplementary M aterial Table of Contents 1 - Online S u pplementary Methods ………………………………………………...… . …2 1.1 Study population……………………………………………………………..2 1.2 Quality control and principal component analysis …………………………..2 1.3 Statistical analyses………………………………………… ………………...3 1.3.1 Disease - specific association testing ……………………………… ..3 1.3.2 Cross - phenotype meta - analysis …………………………………… .3 1.3.3 Model search ……………………………………………………… .4 1.3.4 Novelty of the variants …………………………………………… ..4 1.3.5 Functional Enrichment Analy sis ………………………………… ...4 1.3.6 Drug Target Enrichment Analysis ………………………………… 5 2 - Supplementary Figures………………………………………...………………… . …. 7 3 - Members of the Myositis Genetics Consortium (MYOGEN) ……………………. ..16 4 - Members of the Scleroderma Genetics Consortium ………………… ……………...17 5 - Supplementary References………………………………………………………… . .18 6 - Supplementary Tables………………………………………………………… . ……22 1 Online supplementary m ethods Study population This study was conducted using 12,132 affected subjects and 23 ,260 controls of European des cent population and all of them have been included in previously published GWAS as summarized in Table S1. [1 - 6] Briefly, a total of 3,255 SLE cases and 9,562 ancestry matched controls were included from six countrie s across Europe and North America (Spain, Germany, Netherlands, Italy, UK, and USA). All of the included patients were diagnosed based on the standard American College of Rheumatology (ACR) classification criteria. [7] Previously described GWAS data from 2,363 SSc cases and 5,181 ancestry
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Mozobil (Plerixafor Injection) AHM
    Mozobil (Plerixafor Injection) AHM Clinical Indications • Mozobil (Plerixafor Injection) in combination with granulocyte-colony stimulating factor (G-CSF) is considered medically necessary to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation for patients who have failed a prior mobilization attempts with G-CSF with 1 or more of the following conditions o Lymphoma (i.e., Hodgkin's disease and non-Hodgkin's lymphoma) o Multiple myeloma o Germ cell tumors o WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome • Current role remains uncertain. Based on review of existing evidence, there are currently no clinical indications for this technology. See Inappropriate Uses for more detailed analysis of the evidence base. Mozobil is considered investigational for all other indications Evidence Summary • Background • There has been a steady rise in the use of peripheral blood stem cells (PBSC) as a source of hematopoietic stem cells. In general, less than 0.05 % of white blood cells (WBC) are CD34+ cells. Chemotherapy results in a 5- to 15-fold increase of PBSC. Chemotherapy in combination with growth factors increases CD34+ cells up to 6 % of WBC. In the allogeneic setting, granulocyte-colony stimulating factor (G-CSF) is used alone for mobilization of PBSC. Several factors affect PBSC mobilization; including age, gender, type of growth factor, dose of the growth factor, and in the autologous setting, the patient's diagnosis, chemotherapy regimen and number of previous chemotherapy cycles or radiation. Muscle and bone pain are common side effects in allogeneic stem cell mobilization, but are usually tolerated with the use of analgesics.
    [Show full text]
  • Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression and Radio
    Journal of Nuclear Medicine, published on February 22, 2019 as doi:10.2967/jnumed.118.224048 Combination of 5-Fluorouracil With Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression and Radioligand Binding in Neuroendocrine Tumor Cells in Vitro Xi-Feng Jin1#, Christoph J. Auernhammer1,2*, Harun Ilhan 2,3, Simon Lindner 3, Svenja Nölting1,2, Julian Maurer1, Gerald Spöttl1, Michael Orth4,5,6 1 Department of Internal Medicine 4, University-Hospital Campus Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany 2 Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr, 15, 81377, Munich, Germany. 3 Department of Nuclear Medicine, University-Hospital Campus Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany 4 Department of Radiation Oncology, University Hospital, LMU Munich, Ludwig-Maximilians University of Munich, Munich, Germany 5German Cancer Consortium (DKTK), Munich, Germany 6German Cancer Research Center (DKFZ), Heidelberg, Germany First author# and Corresponding author*: Xi Feng Jin# and Christoph J. Auernhammer*, Department of Internal Medicine 4, University-Hospital Campus Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr, 15, 81377, Munich, Germany. E-mails: [email protected] / [email protected] 1 All authors have contributed significantly, and all authors are in agreement with the content of the manuscript. Disclosure statements: CJA has received research contracts from Ipsen, Novartis, and ITM Solucin, lecture honorarium from Ipsen, Novartis, and Falk Foundation, and advisory board honorarium from Novartis. SN has received research contracts from Novartis and lecture fees from Ipsen. No other potential conflicts of interest relevant to this article exist.
    [Show full text]
  • Orphan Drug Designation List
    Orphan Drug Designations and Approvals List as of 09‐01‐2015 Governs October 1, 2015 ‐ December 31, 2015 Row Contact Generic Name Trade Name Designation Date Designation Num Company/Sponsor 1 (‐)‐(3aR,4S,7aR)‐4‐Hydroxy‐4‐ m‐tolylethynyl‐octahydro‐ Novartis indole‐1‐carboxylic acid Pharmaceuticals methyl ester n/a 10/12/2011 Treatment of Fragile X syndrome Corp. 2 (1‐methyl‐2‐nitro‐1H‐ imidazole‐5‐yl)methyl N,N'‐ bis(2‐broethyl) diamidophosphate n/a 6/5/2013 Treatment of pancreatic cancer EMD Serono 3 (1‐methyl‐2‐nitro‐1H‐ imidazole‐5‐yl)methyl N,N'‐ bis(2‐bromoethyl) Threshold diamidophosphate n/a 3/9/2012 Treatment of soft tissue sarcoma Pharmaceuticals, Inc. 4 (1OR)‐7‐amino‐12‐fluoro‐ 2,10,16‐trimethyl‐15 oxo‐ 10,15,16,17‐tetrahydro‐2H‐8,4‐ Treatment of anaplastic (metheno)pyrazolo[4,3‐ lymphoma kinase (ALK)‐positive h][2,5,11]benzoxadiazacyclote or ROS1‐positive non‐small cell tradecine‐3‐carbonitrile n/a 6/23/2015 lung cancer Pfizer, Inc. 5 (1R,3R,4R,5S)‐3‐O‐[2‐O‐ Treatment of vaso‐occlusive benzoyl‐3‐O‐(sodium(2S)‐3‐ crisis in patients with sickle cell cyclohexyl‐propanoate‐ n/a 2/17/2009 disease. Pfizer, Inc. 6 (1S)‐1‐(9‐deazahypoxanthin‐9‐ yl)‐1,4‐dideoxy‐1,4‐imino‐D‐ Treatment of acute Mundipharma ribitol‐hydrochloride n/a 8/13/2004 lymphoblastic leukemia Research Limited Page 1 of 359 Orphan Drug Designations and Approvals List as of 09‐01‐2015 Governs October 1, 2015 ‐ December 31, 2015 Row Contact Generic Name Trade Name Designation Date Designation Num Company/Sponsor 7 Treatment of chronic lymphocytic leukemia and related leukemias to include (1S)‐1‐(9‐deazahypoxanthin‐9‐ prolymphocytic leukemia, adult T‐ yl)‐1,4‐dideoxy‐1,4‐imino‐D‐ cell leukemia, and hairy cell Mundipharma ribitol‐hydrochloride n/a 8/10/2004 leukemia Research Ltd.
    [Show full text]
  • Macrophages in Nonalcoholic Steatohepatitis: Friend Or Foe?
    Macrophages in Nonalcoholic Steatohepatitis: Friend or Foe? Authors: Joel Grunhut,1 Wei Wang,1 Berk Aykut,1 Inderdeep Gakhal,1 Alejandro Torres-Hernandez,1 *George Miller1,2 1. S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York City, New York, USA 2. Department of Cell Biology, New York University School of Medicine, New York City, New York, USA *Correspondence to [email protected] Disclosure: The authors have declared no conflicts of interest. Received: 14.11.17 Accepted: 28.02.18 Keywords: Inflammation, macrophage, steatohepatitis. Citation: EMJ Hepatol. 2018;6[1]:100-109. Abstract Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease that is characterised by steatosis, chronic inflammation, and hepatocellular injury with or without fibrosis. The role and activation of macrophages in the pathogenesis of NASH is complex and is being studied for possible therapeutic options to help the millions of people diagnosed with the disease. The purpose of this review is to discuss the pathogenesis of NASH through the activation and role of Kupffer cells and other macrophages in causing inflammation and progression of NASH. Furthermore, this review aims to outline some of the current therapeutic options targeting the pathogenesis of NASH. INTRODUCTION The progression to NASH from its less severe form of NAFLD can be predicted by the amount of inflammation present in hepatic tissue.2 Nonalcoholic steatohepatitis (NASH), a subtype Severe inflammation can contribute to the of nonalcoholic fatty liver disease (NAFLD), is progression of other liver diseases, such as one of the most prevalent ongoing liver diseases cirrhosis, fibrosis, and hepatocellular carcinoma.
    [Show full text]