EP0973390A1 - Molecules liees aux retinoides et permettant d'enrayer la surproduction d'endotheline 1 dans l'affection - Google Patents

Molecules liees aux retinoides et permettant d'enrayer la surproduction d'endotheline 1 dans l'affection

Info

Publication number
EP0973390A1
EP0973390A1 EP98914647A EP98914647A EP0973390A1 EP 0973390 A1 EP0973390 A1 EP 0973390A1 EP 98914647 A EP98914647 A EP 98914647A EP 98914647 A EP98914647 A EP 98914647A EP 0973390 A1 EP0973390 A1 EP 0973390A1
Authority
EP
European Patent Office
Prior art keywords
methyl
structures
aryl
retinoid
heteroatom
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98914647A
Other languages
German (de)
English (en)
Other versions
EP0973390A4 (fr
Inventor
Magnus Pfahl
Ju-Yu Hsu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sidney Kimmel Cancer Center
Original Assignee
Sidney Kimmel Cancer Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sidney Kimmel Cancer Center filed Critical Sidney Kimmel Cancer Center
Publication of EP0973390A1 publication Critical patent/EP0973390A1/fr
Publication of EP0973390A4 publication Critical patent/EP0973390A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Retinoids which regulate cell differentiation by modulating gene expression and are thus able to reverse the preneoplastic transformation of cells, have excellent potential as therapeutic agents for the treatment and prophylaxis of cancer (58,59).
  • Retinoids particularly retinoic acid (RA) analogs, have been used in the treatment of leukemia, mycosis fungoides, basal cell carcinoma, psoriasis and other hyperproliferative diseases of the skin (60).
  • RA retinoic acid
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, w-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • Preferred alkyl groups herein contain from 1 to 12 carbon atoms.
  • the term “lower alkyl” intends an alkyl group of from one to six carbon atoms, preferably from one to four carbon atoms, even more preferably one to two carbon atoms.
  • cycloalkyl intends a cyclic alkyl group of from three to eight, preferably five or six carbon atoms.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be defined as -OR where R is alkyl as defined above.
  • a "lower alkoxy” group intends an alkoxy group containing from one to six, more preferably from one to four, carbon atoms.
  • alkylene refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 24 carbon atoms, and includes, for example, methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), propylene (-CH 2 -CH 2 -CH 2 -), 2-methylpropylene [-CH 2 -CH(CH 3 )-CH 2 -], hexylene [-(CH 2 ) 6 -] and the like.
  • “Lower alkylene” refers to an alkylene group of from 1 to 6, more preferably from 1 to 4, carbon atoms.
  • heteroatom refers to sulfur, oxygen, or nitrogen, and preferably sulfur or oxygen.
  • hetero- refers to a compound having at least one heteroatom present in the structural unit, in substitution for a carbon atom.
  • heteroaryl refers to an aryl group having a heteroatom in the aryl ring.
  • ET-1 Diseases that are associated with the presence of increased or elevated levels of ET-1 include any diseases caused by the presence of increased or elevated levels of ET-1, as well as any diseases which cause an overproduction of ET-1.
  • "increased or elevated levels" of ET-1 means levels of ET-1 in a subject, as measured by protocols well known in the art, which are greater than normal levels of ET-1 for the subject, i.e., normal levels of ET-1 are those which are present in a subject in the absence of a disease or pain-associated condition. For example, normal plasma levels of ET-1 in human subjects are described in Nelson et al. (51).
  • the suitable retinoids of this invention are not able to induce differentiation in F9 teratocarcinoma cells and/or PI 9 pluripotent teratocarcinoma cells at a concentration of 10 " 6 M or less.
  • the suitable retinoids of this invention do not exhibit typical retinoid toxicities in vivo and are therefore well tolerated in mammals and humans.
  • retinoids e.g., F9 teratocarcinoma cells and S19 teratocarcinoma pluripotent cells
  • retinoids e.g., F9 teratocarcinoma cells and S19 teratocarcinoma pluripotent cells
  • a decrease in ET-1 production as compared to ET-1 producing cells not contacted with the retinoid and the inability to induce differentiation in cells which differentiate in the presence of retinoids indicating a retinoid suitable for treatment of a subject having a disease or pain-associated condition caused by overproduction of ET-1.
  • the retinoids of the present invention can be administered to human subjects with cancer and other disease or pain-associated conditions caused by elevated levels of ET- 1.
  • the inventive compounds can be administered to human patients diagnosed with prostate cancer (51).
  • the efficacy of the retinoids in these patients can be monitored by assaying such clinical parameters as prostatic serum antigen levels; ET-1 serum or plasma levels; tumor size reduction, weight loss or gain, etc.
  • Such a patient would also be an appropriate subject for evaluating the pain reducing effects of administering the retinoids of the present invention, on the basis that prostate cancer patients, particularly in the later stages of the cancer, experience a significant degree of bone pain, which generally cannot be alleviated by conventional pain- relieving therapies.
  • the efficacy of the inventive compounds in reducing pain in prostate cancer patients can also be determined according to standard methods known in the art for evaluating pain sensation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention porte sur un procédé permettant d'inhiber l'endothéline 1 chez un sujet. Ce procédé consiste en l'administration, au sujet considéré, d'un rétinoïde approprié ou d'une molécule liée aux rétinoïdes, en une quantité suffisante pour provoquer l'inhibition. L'invention concerne également un procédé permettant de soulager la douleur et des affections liées à la présence de niveaux accrus d'endothéline 1 chez des sujets. Ce dernier procédé consiste en l'administration, au sujet considéré, d'un rétinoïde approprié ou d'une molécule liée aux rétinoïdes, en une quantité suffisante pour provoquer l'inhibition de l'endothéline 1.
EP98914647A 1997-04-11 1998-04-10 Molecules liees aux retinoides et permettant d'enrayer la surproduction d'endotheline 1 dans l'affection Withdrawn EP0973390A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4329397P 1997-04-11 1997-04-11
US43293P 1997-04-11
PCT/US1998/007125 WO1998046076A1 (fr) 1997-04-11 1998-04-10 Molecules liees aux retinoides et permettant d'enrayer la surproduction d'endotheline 1 dans l'affection

Publications (2)

Publication Number Publication Date
EP0973390A1 true EP0973390A1 (fr) 2000-01-26
EP0973390A4 EP0973390A4 (fr) 2003-03-19

Family

ID=21926433

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98914647A Withdrawn EP0973390A4 (fr) 1997-04-11 1998-04-10 Molecules liees aux retinoides et permettant d'enrayer la surproduction d'endotheline 1 dans l'affection

Country Status (5)

Country Link
EP (1) EP0973390A4 (fr)
JP (1) JP2001522350A (fr)
AU (1) AU6895198A (fr)
BR (1) BR9808866A (fr)
WO (1) WO1998046076A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69329278T2 (de) * 1992-04-22 2001-08-09 Ligand Pharmaceuticals, Inc. Retinoid-x rezeptor selektive verbindungen
EP1500401A4 (fr) * 2002-04-22 2009-12-23 Res Found Itsuu Lab Medicaments de traitement de maladies vasculaires
EP2910549A1 (fr) 2011-09-15 2015-08-26 Arizona Board of Regents, a Body Corporate of the State of Arizona acting for and on behalf of Arizona State University Dérivés de 1,2,3,4-tétrahydro-1,1,4,4-tétraméthylnaphthalène en tant que modulateur du rxr utiles pour le traitement du cancer et de la maladie d'alzheimer
US10231947B2 (en) 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US10238655B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
US10238626B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021146A1 (fr) * 1992-04-22 1993-10-28 Ligand Pharmaceuticals Incorporated Composes presentant une activite selective par rapport a des recepteurs de retinoide x
US5324840A (en) * 1992-06-11 1994-06-28 Allergan, Inc. Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects
US5455265A (en) * 1993-02-11 1995-10-03 Allergan, Inc. Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors
EP0694301A1 (fr) * 1994-07-27 1996-01-31 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Mélange synergétique d'au moins un ligand spécifique des RXRs et au moins un ligand spécifique de RAR-alpha
EP0747347A1 (fr) * 1995-06-06 1996-12-11 Bristol-Myers Squibb Company Dérivés de l'acide rétino-benzoique ayant une activité RAR-gamma-spécifique
EP0749752A1 (fr) * 1995-06-19 1996-12-27 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Utilisation de ligands spécifiques des récepteurs RXRs

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021146A1 (fr) * 1992-04-22 1993-10-28 Ligand Pharmaceuticals Incorporated Composes presentant une activite selective par rapport a des recepteurs de retinoide x
US5324840A (en) * 1992-06-11 1994-06-28 Allergan, Inc. Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects
US5455265A (en) * 1993-02-11 1995-10-03 Allergan, Inc. Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors
EP0694301A1 (fr) * 1994-07-27 1996-01-31 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Mélange synergétique d'au moins un ligand spécifique des RXRs et au moins un ligand spécifique de RAR-alpha
EP0747347A1 (fr) * 1995-06-06 1996-12-11 Bristol-Myers Squibb Company Dérivés de l'acide rétino-benzoique ayant une activité RAR-gamma-spécifique
EP0749752A1 (fr) * 1995-06-19 1996-12-27 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Utilisation de ligands spécifiques des récepteurs RXRs

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BOEHM M F ET AL: "DESIGN AND SYNTHESIS OF POTENT RETINOID X RECEPTOR SELECTIVE LIGANDS THAT INDUCE APOPTOSIS IN LEUKEMIA CELLS" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 38, no. 16, 4 August 1995 (1995-08-04), pages 3146-3155, XP000615461 ISSN: 0022-2623 *
BOEHM M F ET AL: "SYNTHESIS AND STRUCTURE - ACTIVITY RELATIONSHIPS OF NOVEL RETINOID X RECEPTOR-SELECTIVE RETINOIDS" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 18, 2 September 1994 (1994-09-02), pages 2930-2941, XP000615432 ISSN: 0022-2623 *
DAWSON ET AL: "Conformational Effects on Retinoid Receptor Selectivity. 2. Effects of Retinoid Bridging Group on Retinoid X Receptor Activity and Selectivity" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 38, no. 17, 1995, pages 3368-3383, XP002148373 ISSN: 0022-2623 *
GOTTARDIS, MARCO M. ET AL: "Chemoprevention of mammary carcinoma by LGD1069 (Targretin): an RXR-selective ligand" CANCER RESEARCH ( 1996 ), 56(24), 5566-5570, XP001108852 *
LOPEZ-BOADO, YOLANDA S. ET AL: "Retinoic acid-induced expression of apolipoprotein D and concomitant growth arrest in human breast cancer cells are mediated through a retinoic acid receptor RAR.alpha.-dependent signaling pathway" JOURNAL OF BIOLOGICAL CHEMISTRY ( 1996 ), 271(50), 32105-32111, XP001115034 *
NAKAJIMA, MOTOWO ET AL: "Inhibition by retinoic acid of type IV collagenolysis and invasion through reconstituted basement membrane by metastatic rat mammary adenocarcinoma cells" CANCER RES. ( 1989 ), 49(7), 1698-706, XP008008736 *
See also references of WO9846076A1 *

Also Published As

Publication number Publication date
WO1998046076A1 (fr) 1998-10-22
BR9808866A (pt) 2000-08-01
JP2001522350A (ja) 2001-11-13
EP0973390A4 (fr) 2003-03-19
AU6895198A (en) 1998-11-11

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