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WO1991006589A1 - Nouveaux composes anti-hiv appartenant a l'acide aurintricarboxylique - Google Patents

Nouveaux composes anti-hiv appartenant a l'acide aurintricarboxylique Download PDF

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Publication number
WO1991006589A1
WO1991006589A1 PCT/US1990/006408 US9006408W WO9106589A1 WO 1991006589 A1 WO1991006589 A1 WO 1991006589A1 US 9006408 W US9006408 W US 9006408W WO 9106589 A1 WO9106589 A1 WO 9106589A1
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WIPO (PCT)
Prior art keywords
retention time
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acid
gpc retention
activity
Prior art date
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Ceased
Application number
PCT/US1990/006408
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English (en)
Inventor
Rudiger D. Haugwitz
Venkatachala Narayanan
Marc CUSHMAN
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Purdue Research Foundation
United States Department of Commerce
US Department of Health and Human Services
Original Assignee
Purdue Research Foundation
United States Department of Commerce
US Department of Health and Human Services
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Publication of WO1991006589A1 publication Critical patent/WO1991006589A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
    • C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G8/00—Condensation polymers of aldehydes or ketones with phenols only
    • C08G8/04—Condensation polymers of aldehydes or ketones with phenols only of aldehydes
    • C08G8/08—Condensation polymers of aldehydes or ketones with phenols only of aldehydes of formaldehyde, e.g. of formaldehyde formed in situ

Definitions

  • the present invention is related to the chemical synthesis of a substantially pure monomer of aurintricar- boxylic acid (ATA), structurally defined polymers, analogs and/or derivatives thereof and to defining anti-viral activity of the new compounds, particularly against human immunodeficiency virus (HIV) .
  • ATA aurintricar- boxylic acid
  • HAV human immunodeficiency virus
  • ATA aurintri- carboxylic acid
  • ATA is a potent inhibitor of cellular processes that depend on the binding of nucleic acids to proteins. This inhibition of the binding of nucleic acids to pro ⁇ teins may be due to the fact that the polymeric and polyanionic nature of ATA resembles the structures of oligonucleotides. To the extent that ATA occupies the oligonucleotide binding sites of a wide variety of pro ⁇ teins that normally act on oligonucleotides, it can be regarded as an oligonucleotide mimetic. Examples include the inhibition of protein synthesis by blocking the attachment of mRNA to the ribosome (Grollman et al, Proc. Natl. Acad. Sci. U.S.A.
  • ATA is also known to reduce the affinity of the DNA primer for reverse transcriptase (Givens et al. Nucleic Acids Res. 1976, 3, 405), and to interfere with the activities of DNA (Seki et al, Biochem. Bioohvs. Res. Commun.
  • ATA has recently been shown to block DNA-cellulose binding to progesterone, estrogen, glucocorticoid, and 1.25-dihy- droxyvita ine D3 receptors, suggesting that steroid hormone receptors and nucleic acid polymerase may have similar polynucleotide binding sites (Moudgil et al. Life Sci. 1980, 27, 1159; Moudgil et al, Archs. Biochem. Biophys. 1982, 213, 98; Mellon, Biochem. Pharmacol. 1984, 33, 1047; Moudgil et al. Steroid Biochem. 1985, 23, 125; and Moudgil et al, J. Steroid Biochem. 1985, 22, 747).
  • ATA prevents the cytopathic effect of HIV-1 in ATH8 cell culture as well as the expression of. p24 in H9 cells infected with HIV-1, and it has been suggested that this effect may be due to the inhibition of HIV-1 reverse transcriptase (Balzarini et al, Biochem. Biophys. Res. Commun. 1986, 136, 64) and/or the blockade of the HIV/CD4 cell receptor (Schols et al, Proc. Natl. Acad. Sci. USA 1989, 86, 3322).
  • triphenylmethane dye fuchsin acid As well as ATA, inhibit the cytopathic effect of HIV-1 in MT-4 cell culture (Baba et al, Biochem. Biophys. Res. Commun. 1988, 155, 1404).
  • a still further object of the present invention is to manufacture compounds having greater potency and less cytotoxicity than ATA so as to design drugs that would be useful for the treatment of AIDS and other viral diseases.
  • Figure 1 shows the originally conceived structure of triphenylmethane, and the actual polymeric form of ATA.
  • Figure 2 outlines the syntheses of triphenyl carbinol.
  • Figure 3 outlines the syntheses of 4,4' ,4"- trihydroxy-5,5' ,5"-tricarboxytriphenyl ethane, 5,5',5"- tricarbomethoxy-4,4',4"trihydroxytriphenylmethane, 4,4'- dihydroxy-3,3'-dimethyl-5,5'-dicarboxydiphenylmethane, 5,5 ' ,5"-trimethyl4,4' ,4"-trihydroxy-3,3' ,3"-trimethyl- triphenylcarbinol, and 5,5' ,5"- ricarbomethoxy-4,4' ,4"- trihydroxy-3,3' ,3"-trimethyltriphenylcarbinol.
  • Figure 5 outlines the gel permeation chromatogra ⁇ phy fractionation of ATA.
  • Figure 6 outlines the equilibrium dialylsis and ultrafiltration fractionation of ATA.
  • Figures 7-25 provide in-vitro anti-HIV drug screening results for compounds described herein.
  • DETAILED DESCRIPTION OF THE INVENTION The above and various other objects and advantages of the present invention are achieved by the chemical synthesis of substantially pure monomer, structurally defined polymer, analogs, fractions and derivatives of ATA, preferably having anti-viral and more preferably having anti-HIV activity.
  • substantially pure as used herein means the compound is as pure as can be obtained by conventional isolation and purification means.
  • the temperature was then maintained at 0°C for 1 h before the reaction mixture was left at room temperature (about 22°-24°C) for 24 h.
  • the mixture was poured into crushed ice (150 g) and the precipitate was filtered and dried to give the product 4 (1.7 g, 96%) as a solid.
  • the dialysis was suspended in a water jar and the water was agitated with a magnetic stirrer.
  • the dialysate was replaced with fresh water several times until there was only a very faint color present in the dialysate.
  • the retentate was rotary evaporated.
  • the residue was dried in an Abderhalden drying pistol to obtain 290 mg of the polymeric ammonium salt of aurintri ⁇ phosphonic acid as a dark red glass.
  • the retentate was rotary evaporated and the residue was dried in an Abderhalden drying pistol to afford 330 mg of red glassy solid.
  • the ultra- filtrate was rotary evaporated and the residue was dried in an Abderhalden drying pistol to afford 323 mg of red glassy solid.
  • EXAMPLE 16 Preparation of Polymeric Bromoaurintricarboxylic Acid (22) ATA (1.266 g) was added to glacial acetic acid (50 Ml) and the mixture was cooled in an ice bath. A mixture of bromine (0.8 Ml, density 3.11) in acetic acid (10 Ml) was added dropwise during 30 min. The reaction mixture was then left at room temperature for 22 h. The solvent was removed under reduced pressure and ice (30 g) was added. The precipitate was filtered and dried to yield bromoaurintricarboxylic acid (1.43 g) . Elemental analysis indicated that the brominated polymer contains 28.90% bromine.
  • Triphenyl carbinol 12 (1.0 g) was dissolved in absolute ethanol (100 ML) and the cata ⁇ lyst Pd/C (10%, 0.3 g) was added. The contents were stirred under hydrogen atmosphere at 80 psi for 48 h.
  • Frac ⁇ tionation was accomplished in a series of steps. The first of these involved separating the crude material into two components 1-067.005 and 1-067.004 (See Fig. 5). The second step involved taking these two fractions and dividing them into a second series of four components. This was accomplished by dividing the first two components into two nearly equal parts to yield compounds 1-076.001, 1-076.002, 1-076.003, and 1-076.004. The final step in the fractionation involved repeating this procedure one more time to give eight fractions 1-076.005 - 1-076.012. As is evident from the mean retention times of these eight compounds a separation of the original material based on molecular weight has been accomplished without loss of material. The sample material was converted to solid form by the following procedure.
  • Antiretroviral activity of various compounds was determined by the standard assay employing CEM-V cell line and HIV-1 as the representative infecting agent and was conducted at the National Cancer Institute, Developmental Therapeutics Program, Bethesda, MD. The results are shown in various reports presented herein and made a part hereof. See Figures 7-25.
  • the results presented herein indicate that the synthetic routes and the compounds described herein are useful models for the preparation of a variety of di- and tri-phenylmethanes, ATA analogs and the like which have been exemplified herein by polymeric aurin ⁇ triphosphonic, aurintrisulfonic and bromoaurintricar- boxylic acid, etc., and which possess minimal cytotoxicity but high anti-retroviral activity, particularly against HIV.
  • the methodology described herein can be suitably modified for the preparation of other homogeneous polymers or compounds related to ATA and for the commer- cial scale synthesis by one of ordinary skill in the art.
  • a pharmaceutical composition in accordance with the present invention comprises an effective amount of the compound of the present invention to inhibit cytopathic activity of a retrovirus and a pharmaceutically acceptable carrier.
  • a method of treating retroviral infection comprises contacting retroviral-infected cells with anti ⁇ retroviral amount of the compound of the present inven ⁇ tion.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Synthèse de composés présentant une activité antirétrovirale. La synthèse d'un monomère d'acide aurintricarboxylique pur ainsi que de polymères structurellement définis, d'analogues et de dérivés de ceux-ci, est décrite. On a démontré que les composés présentent une activité antirétrovirale puissante, notamment contre le VIH-1.
PCT/US1990/006408 1989-11-03 1990-11-05 Nouveaux composes anti-hiv appartenant a l'acide aurintricarboxylique Ceased WO1991006589A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43156889A 1989-11-03 1989-11-03
US431,568 1989-11-03

Publications (1)

Publication Number Publication Date
WO1991006589A1 true WO1991006589A1 (fr) 1991-05-16

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PCT/US1990/006408 Ceased WO1991006589A1 (fr) 1989-11-03 1990-11-05 Nouveaux composes anti-hiv appartenant a l'acide aurintricarboxylique

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AU (1) AU6728290A (fr)
WO (1) WO1991006589A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0498240A1 (fr) * 1991-02-02 1992-08-12 Roche Diagnostics GmbH Dérivés de diphénylméthane, procédé pour leur préparation et leur utilisation pour le refoulement de iodothyronines et des protéines les liants
WO1992013542A1 (fr) * 1991-01-31 1992-08-20 Rhone-Poulenc Rorer S.A. Application de polymeres biologiquement actifs pour l'obtention d'un medicament pour le traitement d'infections a retrovirus
EP1007068A4 (fr) * 1997-02-10 2001-04-25 Laub Biochemicals Corp Materiaux synthetiques extraits du sol et medicaments a base de ces materiaux
EP2581080A1 (fr) * 2011-10-13 2013-04-17 Helmholtz-Zentrum für Infektionsforschung GmbH Inhibiteur de la colonisation de la muqueuse

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol. 136, No. 1, issued 14 April 1986, BALZARINI et al., "Aurintricarboxylic Acid and Evans Blue Represent Two Different Classes of Anionic Compounds which Selectively Inhibit the Cytopathogenecity of Human T-Cell Lymphotropic Type III/Lymphadenopathy-Associated Virus", pages 64-71. *
BIOCHEMISTRY AND BIOPHYSICS RESEARCH COMMUNICATIONS, Vol. 155, No. 3, issued 30 September 1988, BABA et al., "Fuschin Acid Selectively Inhibits Human Immunodeficiency Virus (HIV) Replication in Vitro", pages 1404-1411. *
BIOCHEMISTRY, Volume 19, Number 18, issued 02 September 1980, GONZALEZ et al., "Mechanism of Action of Polymeric Aurintricarboxylic Acid, a Potent Inhibitor or Protein-Nucleic Acid Interactions", pages 4299-4303. *
JOURNAL OF MEDICINAL CHEMISTRY, Volume 18, Number 1, issued January 1975, LIAO et al., "Triphenyl Methane Dyes as Inhibitors of Reverse Transcriptase, Ribonucleic Acid Polymerase, and Protein Synthesis. Structure-Activity Relationships", pages 117-120. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA, Volume 86, issued May 1989, SCHOLS et al., "Specific Interaction of Aurintricarboxylic Acid with the Human Immunodeficiency Virus/CD4 Cell Receptor", pages 3322-3326. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013542A1 (fr) * 1991-01-31 1992-08-20 Rhone-Poulenc Rorer S.A. Application de polymeres biologiquement actifs pour l'obtention d'un medicament pour le traitement d'infections a retrovirus
EP0498240A1 (fr) * 1991-02-02 1992-08-12 Roche Diagnostics GmbH Dérivés de diphénylméthane, procédé pour leur préparation et leur utilisation pour le refoulement de iodothyronines et des protéines les liants
EP1007068A4 (fr) * 1997-02-10 2001-04-25 Laub Biochemicals Corp Materiaux synthetiques extraits du sol et medicaments a base de ces materiaux
EP2581080A1 (fr) * 2011-10-13 2013-04-17 Helmholtz-Zentrum für Infektionsforschung GmbH Inhibiteur de la colonisation de la muqueuse
WO2013053881A1 (fr) * 2011-10-13 2013-04-18 Helmholtz-Zentrum für Infektionsforschung GmbH Inhibiteur de la colonisation des muqueuses

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AU6728290A (en) 1991-05-31

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