WO1998050022A1 - Derives d'acide diphenylacetique et leur utilisation comme agents antiviraux - Google Patents

Derives d'acide diphenylacetique et leur utilisation comme agents antiviraux Download PDF

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Publication number
WO1998050022A1
WO1998050022A1 PCT/GB1998/001313 GB9801313W WO9850022A1 WO 1998050022 A1 WO1998050022 A1 WO 1998050022A1 GB 9801313 W GB9801313 W GB 9801313W WO 9850022 A1 WO9850022 A1 WO 9850022A1
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WO
WIPO (PCT)
Prior art keywords
compound
viral
group
viral compound
primary
Prior art date
Application number
PCT/GB1998/001313
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English (en)
Inventor
David John Garnett
Original Assignee
Lovesgrove Research Limited
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
Priority claimed from GBGB9709073.2A external-priority patent/GB9709073D0/en
Priority claimed from GBGB9804337.5A external-priority patent/GB9804337D0/en
Application filed by Lovesgrove Research Limited filed Critical Lovesgrove Research Limited
Priority to AU73433/98A priority Critical patent/AU7343398A/en
Priority to GB9926138A priority patent/GB2340490A/en
Publication of WO1998050022A1 publication Critical patent/WO1998050022A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a new type of anti-viral compound.
  • Viruses are small cellular parasites containing an infectious particle, or virion, which replicate by infecting host cells of other organisms such as plants, animals or bacteria.
  • the viruses are only able to infect a limited range of host cells due to the requirement for an appropriate surface receptor to be present in the membrane of the host cell to which the corresponding protein in the outer capsule of the virus can bind.
  • the nucleic acid typically ends up in the host cell's nucleus where it is replicated using the host cell's machinery for synthesizing proteins and nucleic acids.
  • the proteins produced by the virus are usually special enzymes required for viral replication, inhibitory factors for preventing cell metabolism or proteins for construction of new virions.
  • the cell may lyse to release the particles, causing death of the host cell.
  • the viral nucleic acid may become integrated with the host chromosome such that the viral genome is replicated along with the nucleic acid of the host cell thereby passing the viral nucleic acid from generation to generation.
  • deficiency virus coxsackie B virus, T-cell lymphocyte virus I and respiratory syncytial virus
  • Their ability to integrate with the host's own DNA material increases the difficulty of providing a suitable cure since providing drugs to attack the viral genetic material may also result in damage occurring to the host's own DNA, with possible disastrous consequences, such as carcinogenic effects.
  • HIV human immune deficiency virus
  • This virus enters a human host cell, such as a T4 lymphocyte, by interaction of the glycoprotein gp!20 present in the lipid bilayer membrane of the virus with the plasma membrane receptor CD4 of the host cell. The two membranes are then able to fuse and the viral core is
  • the aforementioned treatments do have their drawbacks.
  • the compounds tend to be highly specific to one particular virus and may also produce adverse side effects.
  • the ability of viruses to mutate as such a rapid rate also means that the virus may quickly become immune to such compositions.
  • Another object of the present invention is to provide an anti-viral agent which may be used in conjunction with other treatment to provide a combined effect.
  • Yet another object of the present invention is to provide an anti-viral agent which is less toxic and has fewer in vivo side effects.
  • an anti-viral compound of a given general formula for use in the treatment of viral infections the general formula being :-
  • Ar 1 and Ar 2 are each either a phenyl group or substituted aromatic group
  • R 1 is a primary, secondary or tertiary alkyl or alkenyl group, a phenyl or hydrogen;
  • R 2 is an alkyl group, a primary, secondary or tertiary alkyl amino group or hydrogen
  • X is C, O, N or S.
  • Ar 1 and Ar 2 are both phenyl groups. Preferred substituents for Ar 1 and Ar 2 when Ar is a substituted aromatic group selected from halide and nitrate groups.
  • R 1 is a primary alkyl group or hydrogen.
  • R 1 is an alkyl group having 1 to 4 carbon atoms, such as a methyl group or a propyl group.
  • R 2 is a primary, secondary or tertiary amino ethyl group, especially being a monoethyl amino ethyl group, a diethylamino ethyl group or an amino ethyl group.
  • R 2 may be hydrogen.
  • Preferred anti-viral compounds of the present invention have the general formula :-
  • R 1 is a primary, secondary or tertiary alkyl group or hydrogen
  • R 2 is an alkyl group, a primary, secondary or tertiary amino alkyl group or hydrogen.
  • a more preferred antiviral compound of the present invention has the formula:-
  • the compounds of the present invention may be used as an anti-viral agent against, for example, the human immune deficiency virus, the respiratory syncytial virus, paramyxoviruses, slow viruses and arenaviruses, such as pichinide and lymphocytic choriomeningitis virus.
  • the compound is administered in doses ranging from l/ g/ml to 100 / zg/ml, preferably 2/- ⁇ g/ml to 50/ig/ml.
  • the compound may be administered orally or by other suitable means, such as injection.
  • the compound may be administered in conjunction with a carrier material.
  • anti-viral compounds of the present invention may be used in combination with other anti-viral agents, such as ribavirin which act at a different stage of the viral infection cycle.
  • the compound may also be administered in conjunction with other substances, such as those acting to reduce inhibition of glucoronyl transferases, monoamine oxidase or cholesterol biosynthesis.
  • R 1 is a primary, secondary or tertiary alkyl group or hydrogen
  • R 2 is an alkyl group, a primary, secondary or tertiary amino alkyl group or hydrogen.
  • the present invention provides a novel compound of the formula:-
  • Ar 1 and Ar 2 are each either a phenyl group or a substituted aromatic group;
  • R 1 is a primary, secondary or tertiary alkyl or alkenyl group, a phenyl or hydrogen;
  • R 2 is an alkyl group, a primary, secondary or tertiary amino alkyl group or hydrogen; and X is C, O, N or S.
  • HIV-1 human immune deficiency virus 1
  • paramyxoviruses paramyxoviruses
  • slowviruses and arenaviruses.
  • SKF-525A (DEDV) and SKF-26754-A (AEPV) have both shown profound inhibition of cytopathic effects following chronic exposure of live cells to low and high viral loads
  • Figure 1 is a graph illustrating the results of an antiviral assay carried out on lymphoblastoid cells infected with HIV IIIB treated with DEDV;
  • Figure 2 is a graph illustrating the cytoxicity levels of lymphoblastoid cells infected with HIV IIIB treated.with DEDV.
  • 2,2-Diphenylpent-4-enoic acid (9.50g, 37.7 mmol) was refluxed with thionyl chloride (20ml) for 8 hours after which the excess thionyl chloride was distilled off to give the crude acid chloride.
  • N-benzyl-N-ethylethanolamine (6.75g, 37.7 mmol) dissolved in pyridine (10ml) and DMF (10ml) was added to the acid chloride and the mixture stirred at room temperature for 24 hours. Water (100ml) was added and the
  • the resultant product was dissolved in methanol (100ml) and 10% palladium on carbon was added. The mixture was hydrogenated at 1 atmosphere of hydrogen
  • 2,2-Diphenylpent-4-enoic acid (9.50g, 37.7 mmol) was refluxed with thionyl chloride (20ml) for 8 hours and any excess thionyl chloride was distilled off to give the crude acid chloride.
  • 2-(diethylamino)ethanol (4.42g, 37.7 mmol) dissolved in
  • 2-(N,N-d ⁇ ethylamu ⁇ o)ethyl 2 2-d ⁇ phenylproponoate was prepared by the same method as 2-(N,N-d ⁇ ethylam ⁇ no)ethyl 2,2-d ⁇ phenylethanoate only using 2,2 diphenylpropiomc acid (5 OOg, 22 1 mmol) as the starting material to give the amine as a light brown liquid (5 85g, 86%) Examples 5 and 6.
  • RS-A2 and RS-N2 Two respiratory syncytial virus isolates from the University Hospital at Aberdeen were used to determine anti-viral activity and are designated RS-A2 and RS-N2.
  • the cell lines used were all sourced from the P.H.L.S, Porton Down, U.K. Media (Minimal Eagles Medium) containing 2% fetal calf serum, and all other media and reagents were, unless otherwise specified, from Sigma Aldrich Ltd, Dorset, U.K.
  • the HIV-IIIb isolate was supplied by St. Bartholomews Hospital, London.
  • the compound DEDV synthesised according to the method described above was tested against each RSV viral isolate at the final concentrations 18.8 ⁇ g/ml and 50 ⁇ g/ml.
  • Sub-confluent HEp-2 cell monolayers were infected with virus and each virus was allowed to absorb for 30 minutes at room temperature before adding fresh media containing either no drug or the drug at the above concentrations.
  • the infected cell monolayers were not washed to remove inoculum (harmless) virus.
  • Virus cpe was determined by visual inspection of the monolayers and scored on a scale of -(no cpe) to 4+ (all cells showing cpe).
  • HIV IIIB (lOTCID's) was used to infect T-lymphoblastoid cells (2 x 10 5
  • FIG. 1 and 2 of the accompanying drawings illustrate respectively the results of the antiviral assay and the cytoxicity levels of the lymphoblastoid cells.
  • the target cells C8166 were incubated in the presence of the agent DEDV for 72 hours.
  • the compound was removed and the labelled protein hydrolysate ( 14 C) was added to the culture for 8 hours. Cells were then harvested and the labelled protein uptake was measured on a scintillation counter. Cut-off for the assay is 50% uptake (CC50) when compared to the positive control, nonoxynol-9.
  • the results are shown below in Table 2 and in Figures 1 and 2 of the accompanying drawings.
  • Examples 5 and 6 indicate that the compounds of the present invention can inhibit the infectivity of the viruses RS-A2, RS-N2 and HIV-1.
  • the compound DEDV and its double N-dealkylated derivative (AEPV) show profound inhibition of cytopathic effects following chronic exposure to live cells to both low and high viral loads. It is likely that the DEDV is metabolically de-alkylated to the -NH 3 moiety in the liver.
  • the toxicity results indicate that the compounds may be provided in non-toxic doses from 2 ⁇ g/ml to 50 ⁇ g/ml dependent upon the cell line used.
  • In vivo acute toxicity of the compounds has not been experienced by experimenters using rats and mice given oral doses of between 50 and 500 mg/kg [Fouts and Brodie 1956].
  • the compounds also remain active in vivo [Axelrod et al 1954] and in studies with male rats dosed i.p. for three days at 50mg/kg the animals did not display signs of acute toxicity [Fernandez et al 1978], although certain in vivo effects have been noted such as the inhibition of glucoronyl transferases, monoamine oxidase and cholesterol biosynthesis. However, these effects may be counteracted by means of a suitable treatment regime. Indeed, DEDV has been used as an anti-cholesterol drug prior hereto but its use as an anti -viral agent has never before been realised.
  • Example 7 Simian Virus 5 (Paramyxovirus).
  • the anti-viral compounds SKF-525-A (DEDV), LR#3, LR#4 and LR#5 were tested to establish their anti viral activity in relation to the Simian Virus 5 acquired from St. Andrews University stock. All the analogues were tested with and without Ribavirin in combination therewith.
  • a six well Linbro plate was seeded with 500,000 Vero cells/well in 10% NBCS medium. After 24 hours the anti-viral compounds were added and left for two hours, prior to the inoculation.
  • a dilution series of the stock viral culture was prepared containing 2% NBCS, medium was removed from Linbro plate and inoculated with 1 ml per well of each dilution onto separate wells.
  • the virus was allowed to absorb for 2-3 hours at 37°C in a CO 2 -gassed box set on a rocking platform. Inoculum was then removed and 10ml of medium containing 2% NBCS 0.5% Methocel and anti-viral agent was added to each well. The residual inoculum was also washed to remove any interferon which the Vero cells may be sensitive to. The plates were then incubated for 10 to 12 days at 37°C in a CO 2 incubator. The medium was then removed and the cells fixed and incubated with 5% formaldehyde, 2% sucrose in PBS for 10 minutes and incubated with 0.5% NP40, 10% sucrose in PBS for 5 minutes. The cells were washed 3 times with PBS containing 1 % calf serum.
  • Plaque levels were quantified using a scanner directly viewing the plates with quantification of plaque density read using "iphotoplus” program.
  • Example 8 Arenaviruses: Pichinde and Lymphocytic choriomeningitis virus (LCMV).
  • LCMV Lymphocytic choriomeningitis virus
  • Triplicate wells of each virus/drug combination were set up, together with three wells which received virus and medium only as a control.
  • the wells were incubated for 1 hour at 37°C, the inoculum was removed and media added back having the appropriate concentration of the anti viral compound.
  • the wells were incubated for a further 48 hours at 37°C and harvested by collecting supernatants.
  • the supernatants were assayed for infectious virus by plaque assay on Vero cell monolayers. Dilutions of the virus were added to confluent cells in 12-well plates, incubated for 1 hour and then removed.
  • the monolayers were overlaid with 199 medium containing 0.6% Oxoid agar and incubated for 3 days.
  • the plaques were counted on day 4 after overlay of plates with 0.3 % neutral red in PBS.
  • DEDV is known to be surface active in artificial membranes [Florence 1970] and has been studied in the context of therapeutic enhancement. Hence, this supports the contention that the compounds act upon the membrane of the host cell.
  • Coxsackie B virus which showed no activity in either viral plaque assay or infected viral titre experiments.
  • CBV Coxsackie B virus
  • the ability of the compounds to act against certain viral agents and not others is explained by the difference in the cell membrane receptor utilised by the virus for attachment to the host cell.
  • the HIV virus binds to the large CD4 protein which is part of the immunoglobin superfamily [Weiss 1994] . It is proposed that this protein, and the alternative cellular attachment site galactoside ceramide [Bhat et al 1991 ; Fantini et al 1993] both require stable membrane conditions to be present before interaction with a viral glycoprotein, such as that of the HIV envelope, is possible.
  • Coxsackie B virus uses a smaller integrin as its viral receptor [Roivainen et al 1994] which may be unaffected by change to its conformation or orientation at the membrane surface.
  • an anti-viral agent which alters the fluidity of the host cell membrane rather than by binding and altering a specific protein results in the agent being able to prevent penetration of the cell membrane by a wider range of viruses, thus providing a broad spectrum anti-viral agent.
  • the agent of the present invention may be used to compliment other treatments.
  • the agent has also been shown to produce low levels of toxicity with the recommended dosages and shows few in vivo effects.
  • the agent has also been shown to produce low levels of toxicity with the recommended dosages and shows few in vivo effects.
  • the agent has also been shown to produce low levels of toxicity with the recommended dosages and shows few in vivo effects.
  • LR#4 is as effective anti-viral agent and demonstrates a low level of toxicity and therefore would appear to be a very useful therapeutic agent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un nouveau composé antiviral à large spectre destiné au traitement d'infections virales, tel que le virus de l'immunodéficience humaine. Le composé présente la formule générale (I) dans laquelle: Ar?1 et Ar2¿ représentent chacun soit un groupe phényle, soit un groupe aromatique substitué; R1 représente un groupe alkyle ou alcényle primaire, secondaire ou tertiaire, un phényle ou un hydrogène; R2 représente un groupe alkyle, un groupe alkylamine primaire, secondaire ou tertiaire ou un hydrogène; et X représente C, O, N ou S. De préférence, les composés comprennent diéthylamino-éthyl-2,2-diphénylvalérate et aminoéthyl-2,2-diphénylvalérate.
PCT/GB1998/001313 1997-05-07 1998-05-06 Derives d'acide diphenylacetique et leur utilisation comme agents antiviraux WO1998050022A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU73433/98A AU7343398A (en) 1997-05-07 1998-05-06 Diphenylacetic acid derivatives and their use as antiviral agents
GB9926138A GB2340490A (en) 1997-05-07 1998-05-06 Diphenylacetic acid derivatives and their use as antiviral agents

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9709073.2 1997-05-07
GBGB9709073.2A GB9709073D0 (en) 1997-05-07 1997-05-07 Broad-spectrum anti-viral
GBGB9720837.5A GB9720837D0 (en) 1997-05-07 1997-10-02 Anti-viral compounds
GB9720837.5 1997-10-02
GB9804337.5 1998-03-03
GBGB9804337.5A GB9804337D0 (en) 1998-03-03 1998-03-03 Anti-viral compounds

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WO1998050022A1 true WO1998050022A1 (fr) 1998-11-12

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GB (1) GB2340490A (fr)
WO (1) WO1998050022A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055112A1 (fr) * 1999-03-18 2000-09-21 Lovesgrove Research Limited Composes anti-viraux
WO2015181837A3 (fr) * 2014-05-30 2016-02-18 Sphaera Pharma Pvt. Ltd. Nouveaux composés utilisés comme agents anti-tuberculeux

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2714376A1 (fr) * 1993-12-29 1995-06-30 Khimbio N,N-diméthylamino-éthyl-beta-(4-hydroxy-3,5-di-tert.-butyl-phényl)-propionates.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2714376A1 (fr) * 1993-12-29 1995-06-30 Khimbio N,N-diméthylamino-éthyl-beta-(4-hydroxy-3,5-di-tert.-butyl-phényl)-propionates.

Non-Patent Citations (12)

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Title
A. KREUTZBERGER ET AL: "Die aliphatische Säureamidgruppierung als Partialstruktur in Virustatika", ARCHIV DER PHARMAZIE, vol. 307, no. 10, 1974, pages 766 - 774, XP002075775 *
BIOCH. BIOPHYS. ACTA, vol. 1042, no. 3, 1990, pages 259 - 364 *
BIOCHEM. PHARMACOL., no. 19, 1970, pages 1025 - 1041 *
BIOCHEM. PHARMACOL., vol. 29, no. 19, 1980, pages 2577 - 2582 *
CHEMICAL ABSTRACTS, vol. 112, no. 15, 9 April 1990, Columbus, Ohio, US; abstract no. 131959y, E. MALVOISIN ET AL: "Effect of drugs which inhibit cholesterol synthesis on syncytia formation in vero cells infected with measles virus" page 24; XP002075780 *
CHEMICAL ABSTRACTS, vol. 68, no. 15, 8 April 1968, Columbus, Ohio, US; abstract no. 66647b, S. AARONSON ET AL: "Effect of hypocholesteremic compounds on bacterial multiplication" page 6420; XP002075779 *
CHEMICAL ABSTRACTS, vol. 73, no. 5, 3 August 1970, Columbus, Ohio, US; abstract no. 23655p, H. SESAME ET AL: "Inhibitory effects of various substances on drug metabolism by liver microsomes: effect of nicotinamide in altering the apparent mechanism of inhibition" page 213; XP002075781 *
CHEMICAL ABSTRACTS, vol. 84, no. 5, 2 February 1976, Columbus, Ohio, US; abstract no. 30682a, G. TSUCHIHASHI ET AL: "Carboxylic acids and esters" page 425; XP002075778 *
CHEMICAL ABSTRACTS, vol. 94, no. 9, 2 March 1981, Columbus, Ohio, US; abstract no. 57860a, P.J.BARBER ET AL: "Micosomal conversion of SKF 525-A and SKF 8742-A" page 12; XP002075782 *
J. GEN. MICROBIOL., vol. 50, no. 1, 1968, pages 271 - 276 *
M. C. LU ET AL: "Molecular modification of anticholinergics as probes for muscarinic receptors. 1. Aminoesters of alpha-substituted phenylacetic acid and related analogs", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 2, 1987, WASHINGTON US, pages 273 - 278, XP002075776 *
T. UEDA ET AL: "Syntheses of 2-acylaminoacetamidine and 3-acylaminopropionamidine derivatives", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 16, no. 12, 1968, pages 2355 - 2361, XP002075777 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055112A1 (fr) * 1999-03-18 2000-09-21 Lovesgrove Research Limited Composes anti-viraux
WO2015181837A3 (fr) * 2014-05-30 2016-02-18 Sphaera Pharma Pvt. Ltd. Nouveaux composés utilisés comme agents anti-tuberculeux
US10100012B2 (en) 2014-05-30 2018-10-16 Sphaera Pharma Pvt. Ltd. Compounds as anti-tubercular agents
US10207993B2 (en) 2014-05-30 2019-02-19 Sphaera Pharma Pvt. Ltd. Compounds as anti-tubercular agents

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AU7343398A (en) 1998-11-27
GB2340490A (en) 2000-02-23
GB9926138D0 (en) 2000-01-12

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