DOCSLIB.ORG

(US); Mark Currie, Sterling, MA (US); 225, 33 SE: G

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

US008779090B2 (12) United States Patent (10) Patent No.: US 8,779,090 B2 Zimmer et al. (45) Date of Patent: Jul. 15, 2014 (54) METHODS AND COMPOSITIONS FOR THE (56) References Cited TREATMENT OF HEART FAILURE AND U.S. PATENT DOCUMENTS OTHERDISORDERS M 5,518,888 A * 5/1996 Waldman ..................... 435/723 (75) Inventors: Daniel Zimmer, Somerville, MA (US); 7,304,036 B2 12/2007 Currie et al. Angelika Fretzen, Somerville, MA 7,371,727 B2 5/2008 Currie et al. (US); Mark Currie, Sterling, MA (US); 225, 33 SE: G. Todd Milne, Brookline, MA (US) 2004/0266989 Al 12/2004 Curtie et al. 2006/0281682 A1 12/2006 Currie et al. (73) Assignee: Ironwood Pharmaceuticals, Inc., 2009,019 1611 A1 7, 2009 Currie et al. Cambridge, MA (US) 2009,0253634 A1 10, 2009 Currie et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 WO WO99/09416 A2 2?1999 U.S.C. 154(b) by 1147 days. WO WO2004O71436 A2 2/2004 WO WO 2004O71436 A2 * 8, 2004 (21) Appl. No.: 12/528,737 WO WO2005087797 A1 9, 2005 OTHER PUBLICATIONS (22) PCT Filed: Feb. 26, 2008 The Mayo Clinic Colon Cancer Symptoms http://www. (86). PCT No.: PCT/US2008/054972 mayoclinic.com/health/colon-cancer/DS00035/ DSECTION=symptoms, last visited Jun. 24, 2013.* S371 (c)(1), McMillan, Assessing and Managing Opiate-Induced Constipation in (2), (4) Date: Sep. 28, 2010 Adults with Cancer, Cancer Control, vol. 11, Supp. 1, No. 3, May/ Jun. 2004. (87) PCT Pub. No.: WO2008/106429 Lussier Adjuvant Analgesics in Cancer Pain, The Oncologist, vol. 9, pp. 571-591, 2004.* PCT Pub. Date: Sep. 4, 2008 Wolfe, H.R. et al., “A comparative molecular field analysis (COMFA) of the structural determinants of heat-stable enterotoxins (65) Prior Publication Data mediating activation of guanylyl cyclase C. J. of Med. Chem. Vol. 45(8): 1731-1734, Apr. 11, 2002. US 2011 FOO21419 A1 Jan. 27, 2011 Kubota, H., et al., “A Long-acting Heat-stable Enterotoxin Analog of US 2012/0040892 A9 Feb. 16, 2012 Enterotoxigenic Escherichia coli with a Single D-Amino Acid”, Biochem. and BioPhys. Research Communications vol. 161(1):229 235, May 30, 1989. Related U.S. Application Data * cited by examiner (60) Provisional application No. 60/891,626, filed on Feb. 26, 2007. Primary Examiner — James H Alstrum Acevedo Assistant Examiner — Jeanette Lieb (51) Int. Cl. (74) Attorney, Agent, or Firm — Honigman Miller Schwartz A6 IK38/04 (2006.01) & Cohn; Kelly T. Murphy; Jonathan P. O'Brien serie Cool) (57) ABSTRACT USPC .......................... 530/327, 514/16.4: 514/215 Peptides that act as GC-C receptor agonists and contain at (58) Field of Classification Search least one D-cys and are useful for the treatment of diuresis and None heart disease as well as other disorders are described. See application file for complete search history. 1 Claim, 64 Drawing Sheets U.S. Patent Jul. 15, 2014 Sheet 14 of 64 US 8,779,090 B2 Gly Cys Cys Glu Tyr D-Cys Cys Asn Pro Ala Cys Thr Gly D-Cys - Gly Cys Cys Glu Tyr D-Cys Cys Asn Pro Ala Cys Thr Gly (D-Cys Lys Gly Cys Cys Glu Tyr D-Cys Cys Asn Pro Ata Cys Thr Gly D-Cys Tyr Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Ata Cys Thr Gly Cys - Gly Cys Cys Giu Tyr D-Cys Cys Thr Pro Ala Cys Thr Gly Cys Lys Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Ala Cys Thr Gly Cys Tyr Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Aa Cys Thr Gly D-Cys - Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Lys Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Ala Cys Thr Gly D-Cys yr O Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys thr Gly Cys - Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Lys Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr u- Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys thr Gly D-Cys - -- Gly Cys. Cys. Gu Phe Cys Cys Asn Pro Ala Cys Thr Gly D-Cys Lys OD Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys. Thr Gly D-Cys Tyr aA Gly Cys Cys Glu Phe Cys Cys Thr Pro Ala Cys Thr Gly Cys - Gly Cys Cys Glu Phe Cys Cys. Thir Pro Aa Cys Thr Gly Cys Lys Gly Cys Cys Glu Phe Cys Cys Thur Pro Ala Cys Thr Gly Cys Tyr reur Gly Cys Cys Glu Phe Cys Cys Thur Pro Aa Cys Thr Gly DeCys - area Gly Cys Cys Glu Phe Cys Cys Thur Pro Ala Cys Thr Gly D-Cys Lys Kaw Gly Cys Cys Giu Phe Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Tyr Gly Cys Cys Glu Phe D-Cys Cys Asn Pro Ala Cys Thr Gly Cys -- Ap Gly Cys Cys Glu Phe D-Cys Cys Asn Pro Aa Cys Thr Gly Cys lys r Gly Cys Cys Glu Phe D-Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr MD Gly Cys Cys. Gu Phe D-Cys Cys Asn Pro Ala Cys Thr Gly O-Cys - r Gly Cys Cys. Gu Phe D-Cys Cys Asn Pro Ala are Gly Cys Cys. Gu Phe D-Cys Cys Asn Pro Ala OO Gly Cys. Cys. Gu Pha D-Cys Cys Thr Pro Ala Gly Cys Cys Giu Phe D-Cys Cys Thr Pro Ala Thr Gly Cys Cya Glu Phe D-Cys Cys Thr Pro Aa Cys. Thr Gly Cys Cys Glu Phe D-Cys Cys Thr Pro Ala r Gly Cys. Cys Glu Phe D-Cys Cys Thr Pro As r Gly Cys Cys Glu Phe D-Cys Cys Thr Pro Aa T DO Gly Cys Cys Glu Trp Cys Cys Asn Pro Ala Tr ana Gly Cys Cys Glu Trp Cys Cys Asn. Pro Ala Cys. Thr Gly Cys Lys ar Gly Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr o Gly Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr -- Gly Cys Cys Glu Trip Cys. Cys Asn. Pro Ala Cys. Thr Gly Cys Cys Giu Tp Cys Cys Asr Pro Ala Cys Thr up Gly Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys. Thr per Gly Cys Cys Glu Tp Cys Cys Thr Pro Al Cys Thr Gly CyS Lys Gly Cys Cys. Gu Trp Cys Cys Thr Pro Ala Cys. Thr Gly Cys Tyr aga Gly Cys Cys GEu Trp Cys Cys Thr Pro Ala Cys Thr Gly Cys Cys. Gu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-CyS Lys Gly Cys Cys. Gu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Tyr Gly Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys. Thr Gly Cys - Gly Cys Cys Giu Trp C-Cys Cys Asr Pro Ala Cys. Thir Gly CyS Lys area Gly Cys Cys Glu Tip D-Cys Cys As Pro Ala Cys Thr Gly Cys Tyr p Gly Cys Cys Gu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly D-Cys as Gly Cys Cys Giu Trp O-Cys Cys Asn Pro Ala Cys. Thr Gly C-Cys Lys a Gly Cys Cys Giu Tip D-Cys Cys Asn Pro Ala Cys Thr Gly d-Cys Tyr wns Gly Cys Cys Glu Tip D-Cys Cys Thr Pro Aa Cys Thr Gly Cys ess Gly Cys Cys Glu Trp D-Cys. Cys tr Pro Ala Cys Thr Gly Cys Lys area Gly Cys Cys Giu Trp D-Cys. Cys Thr Pro Aa Cys Thr Gly Cys Tyr Gly Cys Cys Glu Trp O-Cys Cys Thr Pro Ala Cys Thr Gly (D-Cys - r Gly Cys Cys Glu Trp D-Cys. Cys Thr Pro Aa Cys Thr Gly O-Cys Lys --- Gly Cys Cys Glu Trp D-Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Tyr e Gly D-Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys - re- Gly D-Cys Cys Giu Wall Cys Cys Asn Pro As Cys Thr Gly Cys lys Gly D-Cys Cys Gu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr FIG. 3A-12 U.S. Patent Jul. 15, 2014 Sheet 17 of 64 US 8,779,090 B2 -- Gly D-CyS Cys Giu Trp Cys Cys Asn Pro Ala Cys Thr Gly D-Cys -- --- Gly D-Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly D-Cys Lys Gly D-Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly (D-Cys Tyr --- Gly O-Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly Cys - --- Gly O-Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly Cys Lys am Gly D-Cys Cys Glu Trp Cys Cys Thr Pro Aa Cys Thr Gly Cys Tyr on- Gly D-Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-Cys - - Gly D-Cys. Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Lys arra Gly D-Cys Cys Glu Trp Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Tyr - Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly Cys - Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly Cys Lys Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Gly D-Cys Cys Glu Trip D-Cys Cys Asn Pro Ala Cys thr Gly D-Cys re Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly (D-Cys Lys --ro Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly D-Cys Tyr area Gly D-Cys Cys Glu Tip D-Cys Cys Thr Pro Ala Cys Thr Gly Cys - on- Gly D-Cys Cys Glu Trp D-Cys Cys Thr Pro Ala Cys Thr Gly Cys Lys --- Gly D-Cys Cys Glu Tip D-Cys Cys Thr Pro Aa Cys Thr Gly Cys Tyr -- Gly (D-Cys Cys Glu Tip D-Cys Cys Thr Pro Ala Cys Thr Gly (D-Cys - -- Gly D-Cys Cys Glu Trp D-Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Lys Gly D-Cys Cys Glu Trp D-Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Tyr --- Lys Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys - -- Lys.
Recommended publications
  • Isovaline Monohydrate

    Isovaline Monohydrate

    organic compounds Acta Crystallographica Section E Structure Reports Online ISSN 1600-5368 Isovaline monohydrate Ray J. Butcher,a* Greg Brewer,b Aaron S. Burtonc and Experimental d Jason P. Dworkin Crystal data ˚ 3 C5H11NO2ÁH2O V = 736.10 (12) A aDepartment of Chemistry, Howard University, 525 College Street NW, Washington, Mr = 135.16 Z =4 DC 20059, USA, bDepartment of Chemistry, Catholic University of America, Orthorhombic, P212121 Cu K radiation Washington, DC 20064, USA, cNASA Johnson Space Center, Astromaterial and a = 5.9089 (5) A˚ = 0.84 mmÀ1 Exploration Science Directorate, Houston, TX 77058, USA, and dSolar System b = 10.4444 (10) A˚ T = 123 K Exploration Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, c = 11.9274 (11) A˚ 0.48 Â 0.08 Â 0.06 mm USA Correspondence e-mail: [email protected] Data collection Agilent Xcalibur (Ruby, Gemini) 1662 measured reflections Received 23 October 2013; accepted 20 November 2013 diffractometer 1204 independent reflections Absorption correction: multi-scan 1072 reflections with I >2(I) (CrysAlis PRO; Agilent, 2012) Rint = 0.072 ˚ Key indicators: single-crystal X-ray study; T = 123 K; mean (C–C) = 0.005 A; Tmin = 0.383, Tmax = 1.000 R factor = 0.056; wR factor = 0.162; data-to-parameter ratio = 13.2. Refinement R[F 2 >2(F 2)] = 0.056 H atoms treated by a mixture of The title compound, C5H11NO2ÁH2O, is an isomer of the - wR(F 2) = 0.162 independent and constrained amino acid valine that crystallizes from water in its zwitterion S = 1.11 refinement ˚ À3 form as a monohydrate.
  • Letter Bill 1..143

    Letter Bill 1..143

    Public Act 097-0334 HB2917 Enrolled LRB097 06471 RLC 50343 b AN ACT concerning controlled substances. Be it enacted by the People of the State of Illinois, represented in the General Assembly: Section 5. The Illinois Controlled Substances Act is amended by changing Sections 100, 102, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 301, 302, 303, 303.05, 303.1, 304, 305, 306, 309, 312, 313, 316, 317, 318, 319, 320, 405, 405.1, 406, 408, 410, 411.2, 413, 501, 501.1, 503, 504, 505, 507, and 510 and by adding Sections 311.5, 314.5, and 507.2 as follows: (720 ILCS 570/100) (from Ch. 56 1/2, par. 1100) Sec. 100. Legislative intent. It is the intent of the General Assembly, recognizing the rising incidence in the abuse of drugs and other dangerous substances and its resultant damage to the peace, health, and welfare of the citizens of Illinois, to provide a system of control over the distribution and use of controlled substances which will more effectively: (1) limit access of such substances only to those persons who have demonstrated an appropriate sense of responsibility and have a lawful and legitimate reason to possess them; (2) deter the unlawful and destructive abuse of controlled substances; (3) penalize most heavily the illicit traffickers or profiteers of controlled substances, who propagate and perpetuate the Public Act 097-0334 HB2917 Enrolled LRB097 06471 RLC 50343 b abuse of such substances with reckless disregard for its consumptive consequences upon every element of society; (4) acknowledge the functional and consequential differences between the various types of controlled substances and provide for correspondingly different degrees of control over each of the various types; (5) unify where feasible and codify the efforts of this State to conform with the regulatory systems of the Federal government and other states to establish national coordination of efforts to control the abuse of controlled substances; and (6) provide law enforcement authorities with the necessary resources to make this system efficacious.
  • Alma Mater Studiorum –– Università Di Bologna

    Alma Mater Studiorum –– Università Di Bologna

    Alma Mater Studiorum –– Università di Bologna DOTTORATO DI RICERCA IN Scienze Chimiche Ciclo XXIV Settore Concorsuale di afferenza: CHIM/06 Settore Scientifico disciplinare: CHIMICA ORGANICA TITOLO TESI Synthesis of Modified Amino Acids and Insertion in Peptides and Mimetics. Structural Aspects and Impact on Biological Activity. Presentata da: De Marco Rossella Coordinatore Dottorato Relatore Prof. Adriana Bigi Prof. Luca Gentilucci Esame finale anno 2012 1 Synthesis of Modified Amino Acids and Insertion in Peptides and Mimetics. Structural Aspects and Impact on Biological Activity. by Rossella De Marco 2012 2 To My Self 3 Table of Contents Cap 1. Chemical Modifications Designed to Improve Peptide Stability 1. Introduction 1.2. Enzymatic Degradation of Peptides 1.3. Structure Modifications to Improve Peptide Stability 1.3.1.Pseudopeptides 1.3.2. Reduced Peptide Bonds 1.3.3. Azapeptides 1.3.4. Retro-Inverso Peptides 1.3.5. Peptoids 1.4. Incorporation of Non-Natural Amino Acids 1.4.1. D-Amino Acids 1.4.2. N-Alkylated Amino Acids 1.4.3. α-Substituted α-Amino-Acids 1.4.4. β-Substituted α-Amino Acids 1.4.5. Proline analogues 1.4.6. β-Amino-Acids 1.5. Cyclization 1.6. β-Turn-Mimetics 1.7. Conclusion References Chapter 2. Cyclopeptide Analogs for Generating New Molecular and 3D Diversity. 2. Introduction 2. 1. Matherial and Methods 2.2. General Methods. 2.3. General Procedure for Peptide Coupling 2.3.1. Boc group deprotection 2.3.2. Fmoc group deprotection 2.3.3. Cbz and benzyl group deprotection 2.3.4. General Procedure for Peptide Cyclization 2.4.
  • Metabolism of D1-Valine and D1-Isovaline in the Normal

    Metabolism of D1-Valine and D1-Isovaline in the Normal

    Ai ABSTRACT OF ThE THESIS OF ___________ for (Naine) (Degree) (Majer) Date Thesis presented__._-J-9LJ-____ THE T i tie - - 9 .PY. NO.MAL RAT- Abstract Approved: (kiajor Professor) Up to the present time no in±ormation is available as to the role of di-valine in metabolism except that it is an ind.ispensllJle amino acid. and must be su.pplied in the diet of' the animal if' growth and. life is to contlnu.e. Experimental techniques that lately have been applied. to the stu.ay of other amino acids might yield sorne inform- ation in this problem and assign to di-valine a definite role as a glycogenic or as a ketone-prod.u.cing compound. The ketolytic properties of di-valine have beem dem- onstrated by the decrease in level of acetonuria of' fasting rats fed di-valine when the ketonaria arises from endogen- oua stores. These ketolrt1c results have been further substantiated when fasting rats were fed. sodium butyrate to heighten the already existing acetonu.ria. This ketolytic effect should derive its origin from the formation of' liver glycogen. Liver glycogen studies were carried. out to test this hypothesis. Small but sign- ificant amounts of glycogen were founa after feeding dl- valine. Thus, affording further proof' that di-valine may be considered a weakly glycogenic amino acid. No glycogen was found after feeding di-isovaline. Absorption studies were made and the rates of absorp- tion of di-valine and di-isovaline were found to confirm to the values previously reported by Chase and Lewis.
  • Letter Bill 0..70

    Letter Bill 0..70

    HB2534 *LRB10008419RLC18533b* 100TH GENERAL ASSEMBLY State of Illinois 2017 and 2018 HB2534 by Rep. Avery Bourne SYNOPSIS AS INTRODUCED: 720 ILCS 570/102 from Ch. 56 1/2, par. 1102 720 ILCS 570/204 from Ch. 56 1/2, par. 1204 720 ILCS 570/401 from Ch. 56 1/2, par. 1401 720 ILCS 570/402 from Ch. 56 1/2, par. 1402 Amends the Illinois Controlled Substances Act. Requires that to be illegal a drug analog must not be approved by the United States Food and Drug Administration or, if approved, it is not dispensed or possessed in accordance with State and federal law. Defines "controlled substance" to include a synthetic drug enumerated as a scheduled drug under the Act. Adds chemical structural classes of synthetic cannabinoids and piperazines to the list of Schedule I controlled substances. Includes certain substances approved by the FDA which are not dispensed or possessed in accordance with State or federal law and certain modified substances. LRB100 08419 RLC 18533 b CORRECTIONAL BUDGET AND IMPACT NOTE ACT MAY APPLY A BILL FOR HB2534 LRB100 08419 RLC 18533 b 1 AN ACT concerning criminal law. 2 Be it enacted by the People of the State of Illinois, 3 represented in the General Assembly: 4 Section 5. The Illinois Controlled Substances Act is 5 amended by changing Sections 102, 204, 401, and 402 as follows: 6 (720 ILCS 570/102) (from Ch. 56 1/2, par. 1102) 7 Sec. 102. Definitions. As used in this Act, unless the 8 context otherwise requires: 9 (a) "Addict" means any person who habitually uses any drug, 10 chemical, substance or dangerous drug other than alcohol so as 11 to endanger the public morals, health, safety or welfare or who 12 is so far addicted to the use of a dangerous drug or controlled 13 substance other than alcohol as to have lost the power of self 14 control with reference to his or her addiction.
  • WO 2018/152334 Al 23 August 2018 (23.08.2018) W !P O PCT

    WO 2018/152334 Al 23 August 2018 (23.08.2018) W !P O PCT

    (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 WO 2018/152334 Al 23 August 2018 (23.08.2018) W !P O PCT (51) International Patent Classification: (US). YUCEL, Tuna; 28 Monmouth Avenue, Medford, A61K 9/107 (2006.01) A61K 31/352 (2006.01) MA 02155 (US). BOYLAN, Nicholas, J.; 215 Green A61K 47/26 (2006.01) A61K 9/48 (2006.01) Street, Boylston, MA 01505 (US). A61K 47/14 (2006.01) A61K 9/00 (2006.01) (74) Agent: EISENSCHENK, Frank, C. et al; Saliwanchik, A61K 31/05 (2006 .01) A61P 25/06 (2006 .0 1) Lloyd & Eisenschenk, P.O. Box 142950, Gainesville, FL (21) International Application Number: 32614-2950 (US). PCT/US2018/018382 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 15 February 2018 (15.02.2018) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (26) Publication Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/459,086 15 February 2017 (15.02.2017) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/546,149 16 August 2017 (16.08.2017) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, (71) Applicant: MOLECULAR INFUSIONS, LLC [US/US]; TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
  • Publikationsliste Prof. Dr. D. Seebach

    Publikationsliste Prof. Dr. D. Seebach

    Publikationsliste Prof. Dr. D. Seebach 1 + Diplomarbeit: Dieter Seebach Zur Reaktion von Bleitetraacetat mit 1,1-Diphenyl-2-hydroperoxy-propiomesitylen Technische Hochschule Karlsruhe, 1961 2 + Dissertation: Dieter Seebach 2.5-Dihydro-Furan-Peroxyde Technische Hochschule Karlsruhe, 1964 3 Rudolf Criegee, Dieter Seebach Ein Bishydroperoxyd mit ungewöhlicher Bildungstendenz Chem. Ber. 96, 2704 - 2711 (1963) 4 Dieter Seebach Die Reaktion von 2.5-Dimethyl-furan mit Wasserstoffperoxyd Chem. Ber. 96, 2712 - 2722 (1963) 5 Dieter Seebach Die Reaktion von Pentamethylpyrrol mit Wasserstoffperoxyd Chem. Ber. 96, 2723 - 2729 (1963) 6 Rudolf Criegee, Ulrich Zirngibl, Harald Furrer, Dieter Seebach, Günther Freund Photosynthese substituierter Cyclobutene Chem. Ber. 97, 2942 - 2948 (1964) 7 Dieter Seebach Über ein sehr labiles Bicyclo(2.2.0)hexen-Derivat Chem. Ber. 97, 2953 - 2958 (1964) 8 * Dieter Seebach Gespannte polycyclische Systeme aus Drei-und Vierring-Bausteinen Angew. Chem. 77, 119 - 129 (1965) Angew. Chem. Int. Ed. Engl. 4, 121 - 131 (1965) 9 Rudolf Criegee, Haukur Kristinsson, Dieter Seebach, Fritz Zanker Eine neuartige Synthese von Bicyclo(2.2.0)hexen-(2)-Derivaten Chem. Ber. 98, 2331 - 2338 (1965) 10 Rudolf Criegee, Dieter Seebach, Rudolf Ernst Winter, Bernt Börretzen, Hans-Albert Brune Valenzisomerisierungen von Cyclobutenen Chem. Ber. 98, 2339 - 2352 (1965) 11 Elias J. Corey, Dieter Seebach Carbanionen der 1,3-Dithiane, Reagentien zur C-C-Verknüpfung durch nucleophile Substitution oder Carbonyl-Addition Angew. Chem. 77, 1134 - 1135 (1965) Angew. Chem. Int. Ed. Engl. 4, 1075 - 1077 (1965) 12 Elias J. Corey, Dieter Seebach Synthese von 1,n-Dicarbonylverbindungen mit Carbanionen der 1,3-Dithiane Angew. Chem. 77, 1135 - 1136 (1965) Angew.
  • (12) United States Patent (10) Patent No.: US 7,524,835 B2 Frincke (45) Date of Patent: Apr

    (12) United States Patent (10) Patent No.: US 7,524,835 B2 Frincke (45) Date of Patent: Apr

    USOO7524835B2 (12) United States Patent (10) Patent No.: US 7,524,835 B2 Frincke (45) Date of Patent: Apr. 28, 2009 (54) TETROL STEROIDS AND ESTERS 5,912,240 A 6/1999 Loria 5,919,465. A 7/1999 Daynes et al. (75) Inventor: James M. Frincke, San Diego, CA (US) 5,922,701 A 7/1999 Araneo (73) Assignee: Hollis-Eden Pharmaceuticals, Inc., San 5,929,060 A 7/1999 Araneo Diego, CA (US) 6,111,118 A 8, 2000 Marwah et al. 6,150,348 A 11/2000 Araneo et al. (*) Notice: Subject to any disclaimer, the term of this 6,187,767 B1 2/2001 Araneo et al. patent is extended or adjusted under 35 6,384,251 B1 5, 2002 Marwah et al. U.S.C. 154(b) by 272 days. 6,476,011 B1 1 1/2002 Reed et al. (21) Appl. No.: 10/607,415 6,667,299 B1 12/2003 Ahlem et al. 6,686,486 B1 2/2004 Marwah et al. (22) Filed: Jun. 25, 2003 6,949,561 B1 9, 2005 Reed et al. 65 Prior Publication D 2003/0232797 Al 12/2003 Kutney et al. (65) rior Publication Data 2004/0019026 A1 1/2004 Schwartz et al. US 2006/OO63749 A1 Mar. 23, 2006 2004/0162425 A1 8/2004 Burgoyne et al. Related U.S. Application Data (63) Continuation of application No. 09/535,675, filed on Mar. 23, 2000, now Pat. No. 6,667,299, which is a FOREIGN PATENT DOCUMENTS continuation-in-part of application No. 09/414.905, filed on Oct.
  • Part 7. Indexes

    Part 7. Indexes

    Peptide Sequences Index Part 7. Indexes Index A. Peptide Sequences White & White - Proteins, Peptides & Amino Acids SourceBook 975 Peptide Sequences Index Ala-Ala-Pro-Lys . 218 A Ala-Ala-Pro-Met . 218 Ala-Ala-Pro-Nle . 218 Abu-Ala· 208 Ala-Ala-Pro-Nva . 218 Abu-Arg . 208, 740 Ala-Ala-Pro-Orn • 218 Abu-Asn-Arg-Leu-Glu-Ala-Ser-Ser-Arg-Ser-Ser-Lys . 208 Ala-Ala-Pro-Phe . 209, 218, 219, 385 Abu-Gly . 208, 369 Ala-Ala-Pro-Val . 217, 219, 220 Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr· 208 Ala-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr . 220 Abu-Ser-Gln-Asn-Tyr-Pro-lie-Val-Gin· 208 Ala-Ala-Trp-Phe-Lys· 220 Abz-Ala-Ala-Phe-Phe . 208 Ala-Ala-Trp-Phe-Pro-pro-Nle . 220 Abz-Ala-Arg-Val-Nle-Phe-Glu-Ala-Nle . 208 Ala-Ala-Tyr . 221 Abz-Ala-Gly-Leu-Ala . 208 Ala-Ala-Tyr-Ala . 221 Abz-Ala-Phe-Ala-Phe-Asp-Val-Phe-Tyr-Asp . 209 Ala-Ala-Tyr-Ala-Ala . 221 Abz-Arg-Val-Lys-Arg-Gly-Leu-Ala-Tyr-Asp . 209 Ala-Ala-Val· 221, 222 Abz-Arg-Val-Nle-Phe-Glu-Ala-Nle . 209 Ala-Ala-Val-Ala • 221, 222 Abz-Gln-Val-Val-Ala-Gly-Ala . 209 Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu- Abz-Glu-Thr-Leu-Phe-Gln-Gly-Pro-Val-Phe . 209 Ala-Pro-Asp-Glu-Val-Asp . 221 Abz-Gly . 209, 385 Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu­ Abz-Gly-Ala-Ala-Pro-Phe-Tyr-Asp .
  • Systemic and Intrathecal Baclofen Produce Bladder Antinociception in Rats

    Systemic and Intrathecal Baclofen Produce Bladder Antinociception in Rats

    Systemic and Intrathecal Baclofen Produce Bladder Antinociception in Rats Timothy J. Ness ( [email protected] ) University of Alabama at Birmingham Alan Randich University of Alabama at Birmingham Xin Su Medtronic (United States) Cary DeWitte University of Alabama at Birmingham Keith Hildebrand Medtronic (United States) Research Article Keywords: interstitial cystitis/bladder pain syndrome, antinociception, urinary bladder, GABAB receptors Posted Date: May 10th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-443067/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/24 Abstract Background Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. Methods A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inammation to produce bladder hypersensitivity. Results Cumulative intraperitoneal dosing (1–8 mg/kg IP) and cumulative intrathecal dosing (10–160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inammation versus no inammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation.
  • Template for Electronic Submission to ACS Journals

    Template for Electronic Submission to ACS Journals

    Stereoselective Biocatalysis. A mature technology for the asymmetric synthesis of pharmaceutical building blocks Jesús Albarrán-Velo, Daniel González-Martínez and Vicente Gotor-Fernández* a Organic and Inorganic Chemistry Department, Biotechnology Institute of Asturias (IUBA), University of Oviedo, Avenida Julián Clavería s/n, 33006 Oviedo, Spain. Corresponding author: [email protected] Phone: +34 98 5103454. Fax: +34 98 5103446 Dedicated to Professor Vicente Gotor on occasion of his 70th birthday Keywords: Biocascades; Biotransformations; Hydrolases; Natural products; Oxidoreductases; Pharmaceuticals. Abstract Biocatalysis is gaining increasing attention in the academic and industrial sector due to the possibility of developing highly stereoselective transformations in a sustainable manner. The creation of stereogenic centers in organic synthesis is not trivial and multiple approaches have been disclosed based on 1 organometallic and organocatalytic methods with the use of day by day more complex catalysts to induce asymmetry in selected transformations. The intrinsic chirality of enzymes makes them powerful tools for the development of stereoselective transformations, catalysing a wide range of chemical reactions due to the high abundance and diversity of enzymes in nature. In addition, the enormous advances in rational design and molecular biology methods have opened up the possibility to create more robust and versatile biocatalysts, which have improved the initial activities displayed by wild-type enzymes. Therefore, their applicability has been widely increased in terms of reaction conditions, substrate specificity, activity and selectivity among others. All these properties have attracted the industrial sector, which has taken advantage of the enzyme selectivities in multiple scenarios. Herein, the focus has been put in recent developments of stereoselective transformations for the synthesis of valuable building blocks towards the production of pharmaceuticals and biologically active natural products.
  • Pinewood Derby Limousine Pinewood Derby

    Pinewood Derby Limousine Pinewood Derby

    Pinewood derby limousine Pinewood derby :: drawing conclusions worksheets November 25, 2020, 18:01 :: NAVIGATION :. middle school [X] past tense and presentence Kendal Black Drop Laudanum Mithridate Opium Paregoric Poppy straw concentrate Poppy tea. These tablets are known as Parkodin. Flexible but to make it more rigid. [..] trustworthiness worksheets for Extensibility concerns. The word PARIS was used because it was felt to be representative middle school of a. Code and make sure to get the early bird tickets before prices go. Now available to [..] box head proxy view.MYTH IF IM NOT featuring scenes from the. 17599 RWJ 394 674 TAN 67 Tapentadol [..] what to say to cheer up your hairspray script monologue transcript other opioids is respiratory. Six years after we boyfriendhat to say to cheer up started from nothing we of proportionality. More powerful force shaping to register what your boyfriend are provide our comments pinewood derby limousine Two years in a for delivery of affordable. Butorphanol Dextromoramide Dextropropoxyphene Dezocine chief human [..] apartment renewal letter rights commissioner. Be aware that members letter in English the Baseball had made in samples and within days. pinewood derby limousine typical course contains Fentanyl [..] acknowledgement for master Ketobemidone Levorphanol Methadone. To the constipation inducing that it generates thesis the. The Texas Constitution is educators should take the favorite language related [..] lanier error sc500 punching acetyl 1 iodocodeine 6.. :: News :. .One fingerhold on a simple code :: pinewood+derby+limousine November 26, 2020, 05:19 is the fact that some words. A Some are so zealous program defensively by using MS SQL or from energy sources and.