DOCSLIB.ORG

United States Patent 10) Patent No.: US 8,470,8889 9 B2 Henrich Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent 10) Patent No.: US 8,470,8889 9 B2 Henrich Et Al USOO8470888B2 12 United States Patent 10) Patent No.: US 8,470,8889 9 B2 Henrich et al. (45) Date of Patent: Jun. 25, 2013 (54) BOTRYLLAMIDES AND METHOD OF WO 2006/031614 A2 3, 2006 INHIBITING PGPIN A MAMMAL WO 2008/0392.54 A2 4? 2008 WO 2008/062466 A2 5, 2008 AFFLICTED WITH CANCER WO 2009/088831 A2 T 2009 (75) Inventors: Curtis J. Henrich, Rockville, MD (US); OTHER PUBLICATIONS Heidi R. Bokesch, Frederick, MD (US); ck Laura K. Cartner. Middletown. MD McDonald et al., Tetrahedron, vol. 51, No. 18, pp. 5237-5244. s is Rao et al., J. Nat. Prod., 2004, 67-1064-1066.* (US); Richard W. Fuller, Fairfield, PA McKay et al., Journal of Natural Products (2005), 68(12), 1776 (US); Kirk R. Gustafson, Frederick, AR Belk 1. Anti-C D 17(3), 239-243 (2006) M (US), Kentaro Takada, Yokohama Ahmed-Belkacemetmed-Belkacemet al.,al., Anti-CancerCancer Res., Drugs, 65 (11), 4852-4860 (2005). (JP); James B. McMahon, Frederick, Allen et al., Mol. Cancer Ther:, 1 (6)(6), 417-425 (2002)(2002). MD (US); Susan E. Bates, Bethesda, Alvarez et al., Mol. Pharmacol., 54, 802-814 (1998). MD (US); Robert W. Robey, Laurel, Benderra et al., Clin. Cancer Res., 11 (21), 7764-7772 (2005). MD (US); Suneet Shukla, Rockville, Boumendjel et al., Med. Res. Rev. 25(4), 453-472 (2005). MD (US); Suresh V. Ambudkar Breedveld et al., Cancer Res., 65 (7), 2577-2582 (2005). s A s Damiani et al., Haematologica, 91 (6), 825-828 (2006). Gaithersburg, MD (US); Michael C. Dean et al., Nat. Rev. Cancer. 5, 275-284 (2005). Dean, Frederick, MD (US) Diestra et al., J. Pathol., 198, 213-219 (2002). (73) Assignee: The United States of America, as Henrich et al., J. Biomol. Screen., 11 (2), 176-183 (2006). represented by the Secretary, Henrich et al., Mol. Cancer Ther. 6 (12), 3271-3278 (2007). Holbeck, Eur: J. Cancer, 40, 785-793 (2004). Department of Health and Human Horenstein et al., J. Am. Chem. Soc., 111 (6), 6242-6246 (1989). S ervices, Washington,Wash DC (US)(US Ikeda et al., Int. J. Cancer, 45, 508-513 (1990). (*) Notice: Subject to any disclaimer, the term of this Ikeda, Med. J. Kagoshima Univ. 42 (4), 367-377 (1991), (English patent is extended or adjusted under 35 onkert et al.,1. J.J. Natl. CancerC Inst., 92 (20), 1651-1656 (2000) U.S.C. 154(b) by 259 days. Jonker et al., Proc. Natl. Acad. Sci. USA, 99 (24), 15649-15654 (2002). (21) Appl. No.: 12/811,144 Kim et al., Tetrahedron Letters, 31 (49), 71 19-7122 (1990). Krishnamurthy et al., Annu. Rev. Pharmacol. Toxicol., 46, 381-410 (22) PCT Filed: Dec. 29, 2008 (2006). Kruijtzer et al., J. Clin. Oncol., 20 (13), 2943-2950 (2002). (86). PCT No.: PCT/US2O08/0884.46 Marchand et al., Tetrahedron, 25 (5), 937-954 (1969), (English Abstract). S371 (c)(1), McDonald et al., Tetrahedron, 51 (18), 5237-5244 (1995). (2), (4) Date: Aug. 2, 2010 Oltz et al., J. Am. Chem. Soc., 110 (18), 6162-6172 (1988). Ozvegy-Laczka et al., J. Biol. Chem., 280 (6), 4219-4227 (2005). (87) PCT Pub. No.: WO2009/088831 Phuwapraisirisan et al., Bioorg. Med. Chem. Let., 18 (18), 4956-4958 (2008). PCT Pub. Date: Jul. 16, 2009 (Continued) (65) Prior Publication Data Primary Examiner — Sreeni Padmanabhan US 2010/0317732 A1 Dec. 16, 2010 Assistant Examiner — Svetlana M. Ivanova (74) Attorney, Agent, or Firm — Leydig, Voit & Mayer, Ltd. Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/018.758, filed on Jan. Disclosed are methods of enhancing, the chemotherapeutic 3, 2008 treatment of tumor cells, reducing resistance of a cancer cell s to a chemotherapeutic agent, a method of inhibiting ABCG2, 51) Int. C Pgp, or MRP1 in a mammal afflicted with cancer, and a (51) Int. Cl. method of increasing the bioavailability of an ABCG2 sub A6 IK3I/2 (2006.01) strate drug in a mammal. The methods comprise administer C07C 59/86 (2006.01) ing effective amounts of certain compounds to the mammal, (52) U.S. Cl. for example, a compound of the formula (I): Formula (I), USPC ........................................... 514/679;562/459 wherein R', R. R. X', X, X, a, and b are as described (58) Field of Classification Search herein. Uses of these compounds in the preparation of a None medicament are also disclosed. Also disclosed are com See application file for complete search history. pounds of formula (II), pharmaceutical compositions com prising Such compounds and uses thereof. (56) References Cited (I) U.S. PATENT DOCUMENTS xs×2 4,235,871 A 11/1980 Papahadjopoulos et al. Ro?? sas O 4,501,728 A 2f1985 Geho et al. X4 4,837,028 A 6/1989 Allen 4N-4N 21 SAS 5,019,369 A 5, 1991 Presant et al. H -x FOREIGN PATENT DOCUMENTS ORI 2 EP 1864972 A1 12/2007 OR3 WO O2/O53138 A2 7, 2002 3 Claims, 2 Drawing Sheets US 8,470,888 B2 Page 2 OTHER PUBLICATIONS Shukla et al., Biochemistry, 45 (29), 8940-8951 (2006). Plasschaert et al., Leukemia and Lymphoma, 45(4), 649-654 (2004). Skehan et al., J. Natl. Cancer Inst., 82 (13), 1107-1112 (1990). Price et al., Antimicrobial Agents and Chemotherapy, 161, 95-99 Stewart et al., Cancer Res., 64, 7491-7499 (2004). Stonard et al., Canada J. Chem., 58 (20), 2121-2126 (1980). (1963). Szakács et al., Nat. Rev. Drug Dis., 5 (3), 219-234 (2006). Rabindran et al., Cancer Res., 58, 5850-5858 (1998). Szoka et al., Ann. Rev. Biophys. Bioeng. 9, 467-508 (1980). Rao et al., J. Nat. Prod., 67 (6), 1064-1066 (2004). Takano et al., Pharmacol. Ther. 109, 137-161 (2006). Robey et al., Biochim. Biophys. Acta, 1512, 171-182 (2001). Uggla et al., Leuk Res., 29(2), 141-146 (2005). Robey et al., Br. J. Cancer, 89, 1971-1978 (2003). Wasserman et al., Cancer, 36, 1258-1268 (1975). Robey et al., Cancer Metastasis Rev. 26, 39-57 (2007). Wilson et al., Blood, 108, 685-696 (2006). Robey et al., Cancer Res., 64. 1242-1246 (2004). Xu et al., Curr: Med. Chem., 14, 689-701 (2007). Robey et al., Clin. Cancer Res., 7, 145-152 (2001). Yoh et al., Clin. Cancer Res., 10, 1691-1697 (2004). Sakurai et al., J. Antibio. 55 (8), 685-692 (2002). Zhang et al., J. Antibiot, 60 (3), 204-210 (2007). Sarkadi et al., Physical. Rev. 86, 1179-1236 (2006). Zhang et al., Mol. Pharmacol., 65 (5), 1208-1216 (2004). Scudiero et al., Cancer Res., 48, 4827-4833 (1988). Shoemaker, Nat. Rev. Cancer, 6 (10), 813-823 (2006). * cited by examiner U.S. Patent Jun. 25, 2013 Sheet 1 of 2 US 8,470,888 B2 OH Br MeO O Br MeO MeO O 2 O Br N 2 2 2 2 Br N 2 OMe OH Br N OMe OMe OH botrylamide A botryliamide B botryilamide C OH MeO H Br 2 OMe OH OMe OH OMe botryliamide D botrylamide E botrylamide F Br HO O H Br 2 B.COMe O 2 OHr botrylamide G botrylamide H OH OH MeO Cl-2 O 2 O 2 NC N OMe Out---- OH botrylamide botrylamide J Figure 1 U.S. Patent Jun. 25, 2013 Sheet 2 of 2 US 8,470,888 B2 US 8,470,888 B2 1. 2 BOTRYLLAMIDES AND METHOD OF increasing the bioavailability of an ABCG2 substrate drug in INHIBITING PGPIN A MAMMAL a cancer patient, (v) inhibiting MRP1 in a cancer patient, or AFFLICTED WITH CANCER (vi) inhibiting Pgp in a cancer patient. The invention also provides novel compounds of formula CROSS-REFERENCE TO ARELATED (II), described below, pharmaceutical compositions compris APPLICATION ing Such compounds, and their various uses. This application claims the benefit of U.S. Provisional BRIEF DESCRIPTION OF THE DRAWINGS Patent Application No. 61/018,758, filed Jan. 3, 2008, the disclosure of which is incorporated by reference. 10 FIG. 1 depicts the formulas of certain botrylamides in accordance with an embodiment of the invention. BACKGROUND OF THE INVENTION FIG. 2 depicts a reaction Scheme to prepare compounds of formula (II) in accordance with an embodiment of the inven Multidrug resistance has long been recognized as a major tion: (1) is a condensation reaction; (2) acetylation with acetic obstacle to Successful cancer chemotherapy. The multidrug 15 anhydride and pyridine; (3) dehydration: DMSO, KCO, 98° resistance transporter ABCG2 (or Breast Cancer Resistance Protein 1, BCRP1), a member of the ABC (ATP-binding C.; (4) NaOMe, MeOH, reflux ort-BuOK, THF, -40°C.; (5) cassette) family of membrane transport proteins, is believed octopamine HC1 plus BICA-Na in 60% HSO. to form a part of the maternal-fetal barrier, the blood-brain barrier, and is known to limit oral absorption of Some drugs DETAILED DESCRIPTION OF THE INVENTION (Robey et al., Cancer Metastasis Rev., 26: 39-57 (2007)). The normal physiologic functions of ABCG2 may be related to The invention provides, in accordance with an embodi transport of a variety of natural Substances to prevent intrac ment, a method of enhancing the chemotherapeutic treatment ellular accumulation of toxic compounds. ABCG2 is also an of tumor cells in a mammal with a chemotherapeutic agent, important mediator of resistance to a variety of anti-cancer 25 which method comprises administering to the mammal an drugs, including mitoxantrone, topotecan, irinotecan, fla effective amount of the chemotherapeutic agent in conjunc Vopiridol, and methotrexate (Sarkadi et al., Physiol. Rev., 86: tion with an effective amount of a compound to inhibit 1179-1236 (2006); Krishnamurthy et al., Annu. Rev. Pharma ABCG2 protein, said compound being a compound of for col.
Load more

Recommended publications
  • WO 2017/176265 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2017/176265 A l 12 October 2017 (12.10.2017) P O P C T (51) International Patent Classification: (74) Agent: COLLINS, Daniel W.; Foley & Lardner LLP, A61K 9/00 (2006.01) A61K 9/51 (2006.01) 3000 K Street, NW, 6th Floor, Washington, DC 20007- A61K 47/42 (20 ) 5109 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 16/026270 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 6 April 2016 (06.04.2016) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, EST, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (71) Applicant: MAYO FOUNDATION FOR MEDICAL PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, EDUCATION AND RESEARCH [US/US]; 200 First SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Street, NW, Rochester, Minnesota 55905 (US). TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (72) Inventors: MARKOVIC, Svetomir N.; c/o Mayo Founda (unless otherwise indicated, for every tion For Medical Education And Research, 200 First kind of regional protection available): ARIPO (BW, GH, Street, NW, Rochester, Minnesota 55905 (US).
    [Show full text]
  • In Vitro Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients
    Journal of Cancer Therapy, 2012, 3, 78-89 http://dx.doi.org/10.4236/jct.2012.31011 Published Online February 2012 (http://www.SciRP.org/journal/jct) In Vitro Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients Amal Alotaibi, Adolf Baumgartner, Mojgan Najafzadeh, Eduardo Cemeli, Diana Anderson Division of Biomedical Sciences, University of Bradford, Bradford, UK. Email: [email protected] Received October 12th, 2011; revised November 15th, 2011; accepted December 5th, 2011 ABSTRACT Exposure to toxic chemicals, especially chemotherapeutic drugs, may induce several DNA lesions, including DNA in- terstrand crosslinks. These crosslinks are considered toxic lesions to the dividing cells since they can induce mutations, chromosomal rearrangements, and cell death. Many DNA interstrand crosslinks lesions can be generated by plati- num-based chemotherapeutic agents. Satraplatin is a novel orally administered platinum-based chemotherapeutic agent. In the present study, we investigated DNA interstrand crosslinks lesions induced by oxaliplatin and satraplatin in lym- phocytes obtained from colorectal cancer patients and healthy volunteers. Satraplatin demonstrated an increase in inter- strand crosslinks in a dose-dependent manner in the Comet assay (p < 0.001). In addition, satraplatin and oxaliplatin increased significantly the number of sister chromatid exchanges up to 8.5-fold and 5.1-fold (p < 0.001) respectively, when treated with 2 µM concentration in comparison to untreated colorectal cancer cells. Further, the γH2AX foci for- mation was investigated by an immunofluorescence assay with oxaliplatin and satraplatin. The γH2AX foci formation rate was increased by approximately 9-fold when lymphocytes were treated with 2 μM oxaliplatin.
    [Show full text]
  • Ep 2569287 B1
    (19) TZZ _T (11) EP 2 569 287 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 413/04 (2006.01) C07D 239/46 (2006.01) 09.07.2014 Bulletin 2014/28 (86) International application number: (21) Application number: 11731562.2 PCT/US2011/036245 (22) Date of filing: 12.05.2011 (87) International publication number: WO 2011/143425 (17.11.2011 Gazette 2011/46) (54) COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE VERBINDUNGEN ALS HEMMER DER ATR-KINASE COMPOSÉS UTILISABLES EN TANT QU’INHIBITEURS DE LA KINASE ATR (84) Designated Contracting States: • VIRANI, Aniza, Nizarali AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Abingdon GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Oxfordshire OX144RY (GB) PL PT RO RS SE SI SK SM TR • REAPER, Philip, Michael Abingdon (30) Priority: 12.05.2010 US 333869 P Oxfordshire OX144RY (GB) (43) Date of publication of application: (74) Representative: Coles, Andrea Birgit et al 20.03.2013 Bulletin 2013/12 Kilburn & Strode LLP 20 Red Lion Street (73) Proprietor: Vertex Pharmaceuticals Inc. London WC1R 4PJ (GB) Boston, MA 02210 (US) (56) References cited: (72) Inventors: WO-A1-2010/054398 WO-A1-2010/071837 • CHARRIER, Jean-Damien Abingdon • C. A. HALL-JACKSON: "ATR is a caffeine- Oxfordshire OX144RY (GB) sensitive, DNA-activated protein kinase with a • DURRANT, Steven, John substrate specificity distinct from DNA-PK", Abingdon ONCOGENE, vol. 18, 1999, pages 6707-6713, Oxfordshire OX144RY (GB) XP002665425, cited in the application • KNEGTEL, Ronald, Marcellus Alphonsus Abingdon Oxfordshire OX144RY (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Cisplatin Induced Hearing Loss in Paediatric Malignancies
    CISPLATIN INDUCED HEARING LOSS IN PAEDIATRIC MALIGNANCIES 1 CISPLATIN INDUCED HEARING LOSS IN PAEDIATRIC MALIGNANCIES A DISSERTATION SUBMITTED IN PARTIAL FULFILMENT OF M.S BRANCH IV OTORHINOLARYNGOLOGY EXAMINATION OF THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY TO BE HELD IN APRIL 2016 2 DEPARTMENT OF OTORHINOLARYNGOLOGY CHRISTIAN MEDICAL COLLEGE VELLORE DECLARATION I declare that this dissertation entitled “Cisplatin induced hearing loss in Paediatric malignancies’’ submitted towards fulfilment of the requirements of the Tamil Nadu Dr. M.G.R. Medical University for the MS Branch IV, Otorhinolaryngology examination to be conducted in April 2016, is the bonafide work of Dr. Susana Mathew, postgraduate student in the Department of Otorhinolaryngology, Christian Medical College, Vellore Dr. Susana Mathew Postgraduate Student (M S Otorhinolaryngology ) Register Number: 221314355 Department of Otorhinolaryngology Christian Medical College Vellore. 3 DEPARTMENT OF OTORHINOLARYNGOLOGY CHRISTIAN MEDICAL COLLEGE VELLORE CERTIFICATE This is to certify that the dissertation entitled “Cisplatin induced hearing loss in paediatric malignancies’’ is a bonafide original work of Dr. Susana Mathew, submitted in partial fulfilment of the rules and regulations for the M S Branch IV, Otorhinolaryngology examination of The Tamil Nadu Dr. M.G.R. Medical University to be held in April 2016. Principal Head Of Department Dr. Alfred Job Daniel Dr. John Mathew Christian Medical College Professor and Head, Vellore- 632002 Department of Otorhinolaryngology, India. Christian Medical College, Vellore. 4 DEPARTMENT OF OTORHINOLARYNGOLOGY CHRISTIAN MEDICAL COLLEGE VELLORE CERTIFICATE This is to certify that the dissertation entitled “Cisplatin induced hearing loss in paediatric malignancies’’ is a bonafide original work of Dr. Susana Mathew, submitted in partial fulfilment of the rules and regulations for the M S Branch IV, Otorhinolaryngology examination of The Tamil Nadu Dr.
    [Show full text]
  • Copyrighted Material
    Index 232 tet 42–3 antidiabetic drugs 219–30 antimalarials 211 AAS see atomic absorption spectroscopy AOs see atomic orbitals Ab peptide 230, 232–5 APL see acute promyelocytic leukemia absorption spectra 16–28 apoferritin 292–3 band assignments 24–8 APP see amyloid precursor protein band intensity/selection rules 19–21, 26–7 area under curve (AUC) 113–14, 157 Beer–Lambert law 17–18 arginine 51 carboplatin 110–11, 114 Arrhenius equation 34–5 cisplatin 75–6 arsenic trioxide (ATO) 290–2 crystal field theory 17–18, 20–8 ascorbic acid 155–6, 157–8 gold compounds 192, 205, 209–10 asparagine 51 group theory 22 aspartic acid 51, 53 Jahn–Teller distortions 18–19, 20 associative mechanism 35–6, 41 oxaliplatin 129 ATO see arsenic trioxide ruthenium anticancer drugs 157, 159–60 atomic absorption spectroscopy (AAS) 66–7, 114 spectroscopic/free ion terms 20–4 atomic orbitals (AOs) 11–16 splitting parameters 24–8 ATP7A/B protein mutations 84, 87, 235, 236 Tanabe–Sugano diagrams 22–6, 27 AUC see area under curve titanium III hexahydrate 17–19 auranofin 193–200, 203–5 vanadium antidiabetic drugs 220, 223–7 aurocyanide 210–11 accelerator mass spectrometry (AMS) 132 aurothioglucose 193–4 acquired immunodeficiency syndrome see HIV/AIDS aurothiosulfate 193–4 acquired resistance 118, 158 activation by reduction hypothesis 155 b-cyclodextrin 270–1 acute promyelocytic leukemia (APL) 290–2 b-sheets 51, 202, 204 adenine 58–9 BBR3464 137, 140–1 Alzheimer disease (AD) 230–5, 257–8 BCM-ESR see blood-circulation monitoring–electron AMD3100 238–42 spin resonance Ames
    [Show full text]
  • Audrey Dang, Et Al. V. GPC Biotech AG, Et Al. Dang-Class Action Complaint
    UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF NEW YORK AUDREY DANG, Individually and On Behalf of ) All Others Similarly Situated, ) CIVIL ACTION NO. Plaintiff, ) vs. CLASS ACTION COMPLAINT GPC BIOTECH AG, BERND SEIZINGER, M.D., PH.D., MARTINE GEORGE, M.D., and MARCEL JURY TRIAL DEMANDED ROZENCWEIG, M.D., Defendants. ) Plaintiff, Audrey Dang, ("Plaintiff'), alleges the following based upon the investigation by Plaintiffs counsel, which included, among other things, a review of the defendants' public documents, conference calls and announcements made by defendants, United States Securities and Exchange Commission ("SEC") filings, wire and press releases published by and regarding GPC Biotech AG ("GPC" or the "Company"), securities analysts' reports and advisories about the Company, and information readily available on the Internet, and Plaintiff believes that substantial additional evidentiary support will exist for the allegations set forth herein after a reasonable opportunity for discovery. NATURE OF THE ACTION AND OVERVIEW 1. This is a federal class action on behalf of purchasers of GPC's securities between December 5, 2005 and July 24, 2007, inclusive (the "Class Period"), seeking to pursue remedies under the Securities Exchange Act of 1934 (the "Exchange Act") 1 2. GPC is a biopharmaceutical company engaged in the discovery, development and commercialization of new drugs to treat cancer. During the Class Period, the Company's lead product candidate was satraplatin, an orally administered platinum-based compound intended for use as a chemotherapy treatment. 3. Prior to, and throughout the Class Period, GPC reported positive test results in the evaluation of satraplatin. Further, the Company repeatedly stated that satraplatin showed promising safety and efficacy as demonstrated by "significant improvement" in progression-free survival ("PFS") in a randomized study of first-line treatment of patients with hormone- refractory prostate cancer ("HRPC").
    [Show full text]
  • Spectrum Pharmaceuticals Announces the Expansion by Its
    Spectrum Pharmaceuticals Announces the Expansion by its Partner of Satraplatin Phase 3 Registrational Trial in Europe after It Received 'Scientific Advice' Letter from European Drug Regulatory Authority The Same Phase 3 Registrational Trial Will Be Used in Both Europe and the United States, Where Satraplatin Was Granted Fast Track Designation by the FDA IRVINE, Calif., Feb. 3 /PRNewswire-FirstCall/ -- Spectrum Pharmaceuticals, Inc. (Nasdaq: SPPI) today announced that Spectrum Pharmaceuticals' co- development partner for satraplatin, GPC Biotech AG (Frankfurt Stock Exchange: GPC), has received a Scientific Advice Letter from the European Agency for the Evaluation of Medicinal Products (EMEA) enabling the Phase 3 registrational trial on satraplatin to proceed in Europe using the SPARC (Satraplatin and Prednisone Against Refractory Cancer) trial. The multi-center, global, randomized SPARC trial is designed to evaluate satraplatin plus prednisone versus placebo plus prednisone as a second-line chemotherapy regimen for treating patients with hormone-refractory prostate cancer (HRPC). The primary endpoint of the trial is based upon disease progression. The SPARC trial was initiated in the U.S. in September 2003, following successful completion of a Special Protocol Assessment (SPA) and an "End of Phase 2" meeting with the U.S. Food and Drug Administration (FDA). The provision of Scientific Advice is one of the tasks of the EMEA whereby companies are advised on the conduct of various tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal products. Such advice is important for the success of registrational clinical trials in Europe and helps to establish a meaningful dialogue between the EMEA and a Sponsor.
    [Show full text]
  • View Annual Report
    Spectrum Pharmaceuticals, Inc. CANCER TAKES THE LIVES OF OVER SEVEN MILLION PEOPLE WORLDWIDE EACH YEAR www.spectrumpharm.com 157 Technology Drive, Irvine, California 92618 Telephone 949.788.6700 2005 Annual Report spECTRUM PHARMACEUTicALS, INC. SPECTRUM O U R T E A M PHARMACEUTicALS BOARD OF DIRECTORS MANAGEMENT TEAM OUTSIDE COUNSEL Rajesh C. Shrotriya, M.D. Rajesh C. Shrotriya, M.D. Latham & Watkins LLP Chairman of the Board, Chief Executive Officer Chairman, Chief Executive Officer & President Costa Mesa, California is COMMITTED TO & President, Spectrum Pharmaceuticals, Inc. Luigi Lenaz, M.D. I NDEPENDENT A UDITORS Richard D. Fulmer, M.B.A. Chief Scientific Officer Kelly & Company Former Vice President, Licensing and Development, Costa Mesa, California IMPROVING THE and Vice President of Marketing, Pfizer Inc. Shyam K. Kumaria, CPA, MBA Vice President, Finance T R A N S F E R A GENT Stuart M. Krassner, Sc.D., Ph.D. U.S. Stock Transfer Corporation LIVES OF PEOPLE Professor Emeritus of Developmental and Russell L. Skibsted Glendale, California Cell Biology at the School of Biological Sciences Senior Vice President, Chief Business Officer University of California at Irvine SEC F O R M 1 0 - K Ashok Y. Gore, Ph.D. Please see the enclosed Annual Report on Form WHO ARE FIGHTING Anthony E. Maida, III, M.A., M.B.A. Senior Vice President, Pharmaceutical 10-K filed with the Securities and Exchange Chairman, BioConsul Drug Development Operations & Regulatory Compliance Commission for a more detailed description Corporation and DendriTherapeutics, Inc. of the Company’s business, financial and other Consultant to various Venture Capital, William N.
    [Show full text]
  • The Personalized Medicine Report
    THE PERSONALIZED MEDICINE REPORT 2017 · Opportunity, Challenges, and the Future The Personalized Medicine Coalition gratefully acknowledges graduate students at Manchester University in North Manchester, Indiana, and at the University of Florida, who updated the appendix of this report under the guidance of David Kisor, Pharm.D., Director, Pharmacogenomics Education, Manchester University, and Stephan Schmidt, Ph.D., Associate Director, Pharmaceutics, University of Florida. The Coalition also acknowledges the contributions of its many members who offered insights and suggestions for the content in the report. CONTENTS INTRODUCTION 5 THE OPPORTUNITY 7 Benefits 9 Scientific Advancement 17 THE CHALLENGES 27 Regulatory Policy 29 Coverage and Payment Policy 35 Clinical Adoption 39 Health Information Technology 45 THE FUTURE 49 Conclusion 51 REFERENCES 53 APPENDIX 57 Selected Personalized Medicine Drugs and Relevant Biomarkers 57 HISTORICAL PRECEDENT For more than two millennia, medicine has maintained its aspiration of being personalized. In ancient times, Hippocrates combined an assessment of the four humors — blood, phlegm, yellow bile, and black bile — to determine the best course of treatment for each patient. Today, the sequence of the four chemical building blocks that comprise DNA, coupled with telltale proteins in the blood, enable more accurate medical predictions. The Personalized Medicine Report 5 INTRODUCTION When it comes to medicine, one size does not fit all. Treatments that help some patients are ineffective for others (Figure 1),1 and the same medicine may cause side effects in only certain patients. Yet, bound by the constructs of traditional disease, and, at the same time, increase the care delivery models, many of today’s doctors still efficiency of the health care system by improving prescribe therapies based on population averages.
    [Show full text]
  • Spectrum Pharmaceuticals Announces Start of Phase 2 Trial Evaluating Satraplatin Plus Taxol(R) in Patients with Advanced Non-Small Cell Lung Cancer
    Spectrum Pharmaceuticals Announces Start of Phase 2 Trial Evaluating Satraplatin Plus Taxol(R) in Patients With Advanced Non-Small Cell Lung Cancer * Open label study being led by investigators at the Sarah Cannon Research Institute in Nashville, Tennessee * Phase 2 study evaluating the Company's lead drug candidate, satraplatin, in combination with Taxol® IRVINE, Calif., Dec 09, 2005 /PRNewswire-FirstCall via COMTEX News Network/ -- Spectrum Pharmaceuticals, Inc. (Nasdaq: SPPI) today announced the opening of accrual of a Phase 2 study evaluating the Company's lead drug candidate, satraplatin, in combination with Taxol® (paclitaxel) as a first-line therapy in patients with unresectable advanced non-small cell lung cancer (NSCLC). Satraplatin is currently in a Phase 3 registrational trial as a second-line chemotherapy treatment for patients with hormone-refractory prostate cancer. New clinical studies to explore the potential of satraplatin in a number of additional tumor types are also being planned. The Phase 2 study in advanced NSCLC is an open label study being led by investigators at the Sarah Cannon Research Institute (SCRI) in Nashville, Tennessee. The study will also be open for accrual in their affiliated network of oncologists, Tennessee Oncology. The primary objective of this study is to determine the objective response rate of satraplatin in combination with Taxol in this patient population. The study will also evaluate time to progression and overall survival. The study is expected to enroll up to 40 patients. "I look forward to further exploring the potential of satraplatin with Taxol in the advanced lung cancer setting, as this new study builds on the Phase 1 study my team did with this combination," said F.
    [Show full text]
  • Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and in Vitro Research on Their Cytotoxic Activity
    pharmaceuticals Article Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and In Vitro Research on Their Cytotoxic Activity Henryk Mastalarz 1,*, Agnieszka Mastalarz 2, Joanna Wietrzyk 3 , Magdalena Milczarek 3 , Andrzej Kochel 2 and Andrzej Regiec 1 1 Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, 211A Borowska Street, 50-556 Wrocław, Poland; [email protected] 2 Faculty of Chemistry, The University of Wrocław, 14F Joliot-Curie Street, 50-383 Wrocław, Poland; [email protected] (A.M.); [email protected] (A.K.) 3 Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl Street, 53-114 Wrocław, Poland; [email protected] (J.W.); [email protected] (M.M.) * Correspondence: [email protected]; Tel.: +48-717840347; Fax: +48-717840341 Received: 6 October 2020; Accepted: 25 November 2020; Published: 28 November 2020 Abstract: A series of eight novel platinum(II) complexes were synthesized by the reaction of the appropriate 1-methylnitropyrazole derivatives with K2PtCl4 and characterized by elemental analysis, ESI MS spectrometry, 1H NMR, 195Pt NMR, IR and far IR spectroscopy. Thermal isomerization of cis-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 1 to trans-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 2 has been presented, and the structure of the compound 2 has been confirmed by X-ray diffraction method. Cytotoxicity of the investigated compounds was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian and A-549 lung adenocarcinomas) and their logP was measured using a shake-flask method.
    [Show full text]