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WO1997027200A1 - Derives de la thienoxazinone utiles comme agents antiviraux - Google Patents

Derives de la thienoxazinone utiles comme agents antiviraux Download PDF

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Publication number
WO1997027200A1
WO1997027200A1 PCT/EP1997/000367 EP9700367W WO9727200A1 WO 1997027200 A1 WO1997027200 A1 WO 1997027200A1 EP 9700367 W EP9700367 W EP 9700367W WO 9727200 A1 WO9727200 A1 WO 9727200A1
Authority
WO
WIPO (PCT)
Prior art keywords
thieno
oxazin
methyl
aminoethyl
trans
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.)
Ceased
Application number
PCT/EP1997/000367
Other languages
English (en)
Inventor
Richard Lewis Jarvest
Leslie John Arthur Jennings
Ivan Leo Pinto
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 GBGB9601546.6A external-priority patent/GB9601546D0/en
Priority claimed from GBGB9610909.5A external-priority patent/GB9610909D0/en
Priority claimed from GBGB9612937.4A external-priority patent/GB9612937D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to AU15959/97A priority Critical patent/AU1595997A/en
Publication of WO1997027200A1 publication Critical patent/WO1997027200A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which are of potential use as antiviral agents.
  • WO 96/19482 (SmithKline Beecham pic) describes 2-substituted herpesvirus protease inhibitor 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives.
  • herpesviruses especially herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, and varicella-zoster virus.
  • the present invention provides herpesvirus protease inhibitor 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives which are:
  • R 1 is hydrogen or an amino acid side chain
  • the 5-substituent is methyl and the 6-substituent is CH 2 R a , OCH 2 R b , or NR c R d wherein R a and R b are selected from hydrogen or a substituent, R c is alkyl and R d is alkyl or substituted alkyl or R c and R d are joined to form a heterocyclic ring containing one or more heteroatoms.
  • R a and R b may be selected from one or more of halo, trifluoromethyl, cyano, alkyl, alkoxy, aryloxy, aryl(alkyl)oxy, alkylthio, amino optionally substituted by one or two alkyl or optionally substituted benzyl groups, hydroxy, alkylcarbonyl, alkoxycarbonyl, trifluoromethylcarbonyl, optionally substituted phenyl or R e ZCOY wherein Z is a bond, O, NH or NCOCH 3 , and R e CO is an acyl group where values of R e include aryl, alkyl, aralkyl, or heteroaryl-alkyl; and Y is O or NR f wherein R f is hydrogen, alkyl, aryl, or aralkyl, or R e and R f may together form C 2-6 polymethylene; or R a /R b may be alkyl or alkeny
  • R d substituents are as defined for R a and R b above. Values for R c and R d when joined to form a heterocyclic ring include optionally substituted piperidine, pyrrolidine, azetidine morpholine, or piperazine. Suitable substituents are as listed above for R a and R b , or the heterocyclic ring may contain an exocyclic optionally protected carbonyl group.
  • alkyl or alkyl containing groups examples include C 1 , C 2 , C 3 , C 4 , C 5 ,
  • C 6 branched, straight chained and/or cyclic and/or primary, secondary or tertiary alkyl, as appropriate.
  • C 1 -4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl.
  • Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Alkenyl includes all suitable values including E and Z forms.
  • Aryl includes phenyl and naphthyl optionally substituted by one or more substituents.
  • substituents may be selected from halo, C 1 -6 alkyl, C 1 -6 alkoxy,
  • Heteroaryl includes 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon.
  • Monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possible isomers).
  • Bicyclic heteroaryl include benzofuranyl,
  • Heteroaryl may be optionally substituted by one or more substituents. These may be selected from those described above for aryl substituents.
  • Halo includes fluoro, chloro, bromo and iodo.
  • amino acid side chain may be of one or more amino acids. Suitable examples of amino acids are as described in the literature relating to synthetic peptides and includes natural and 'unnatural' amino acids.
  • the amino acids may be in the D or L form, preferably the L form. Particular aminoacyl moieties
  • the compounds of formula (I) including their pharmaceutically acceptable salts may form solvates such as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • the compounds are prepared by activating an R 1 containing amino acid derivative by standard peptide procedures such as:
  • the intermediate amide may be isolated or the crude reaction product cyclised directly.
  • Reagents suitable for the cyclisation of the thiophene acid derivatives include coupling agents or dehydrating agents such as carbodiimides, acetic anhydride or sulphonyl chlorides.
  • Reagents suitable for the cyclisation of the thiophene ester derivatives include triphenylphosphine/carbon tetrachloride. If the amino acid has a functionalised side-chain with a protecting group, then a final stage is the removal of the protecting group, for example, the removal of an acid-labile group with trifluoroacetic acid.
  • the optionally present amino protecting group can be removed and the free amine or its salt can be acylated by an acid R 4 COOH or derivative.
  • Suitable coupling agents would include those described in i) and ii) above and derivatives would include the acid chloride and the anhydride. It will be appreciated that according to the nature of the 5- and 6- substituents in the required product, the cyclisation may occur prior to or after introduction/modification of the relevant substituent(s).
  • compositions may be prepared in conventional manner, for example, in the case of acid addition salts, by reaction with the appropriate organic or inorganic acid.
  • the compounds of the invention are of potential use in the treatment of infections caused by herpesviruses such as herpes simplex types 1 and 2,
  • a pharmaceutical composition which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient.
  • a composition which may be administered by the oral route to humans may be compounded in the form of a syrup, tablet or capsule.
  • any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension.
  • Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups.
  • the compounds may also be presented with a sterile liquid carrier for injection.
  • composition may possibly also be formulated for topical application to the skin or eyes.
  • the composition may be in the form of a cream, lotion or ointment.
  • These formulations may be conventional formulations well known in the art, for example, as described in standard books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books and the British Pharmacopoeia.
  • composition for application to the eyes may be a conventional eye-drop composition well known in the art, or an ointment composition.
  • the composition of this invention is in unit dosage form or in some other form that may be administered in a single dose.
  • a suitable dosage unit might contain from 50 mg to 1 g of active ingredient, for example 100 to 500 mg.
  • Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day.
  • the effective dose of compound will in general be in the range of from 1.0 to 20 mg/kg of body weight per day or more usually 2.0 to 10 mg/kg per day.
  • the invention also provides a method of treating viral infections in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for the treatment of viral infections.
  • R has the following values:
  • dichloromethane (1 ml) was treated with 1-hydroxybenzotriazole (75 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (105 mg, 0.55 mmol) in dichloromethane (2 ml) and stirred for 0.5 h.
  • a solution of inhibitor is added to a solution of enzyme (0.5 - 1 uM) diluted in buffer (50 mM sodium phosphate, 150 mM sodium chloride, 0.001 mM EDTA, 0.01% PEG 3400; pH 8.0) to give a final inhibitor concentration of 0.01 to 300 uM in a total volume of 25 microliters.
  • buffer 50 mM sodium phosphate, 150 mM sodium chloride, 0.001 mM EDTA, 0.01% PEG 3400; pH 8.0
  • 15 microliters of a solution of the 14-mer peptide substrate, Ac-HTYLQASEKFKMWG is added to give a final substrate concentration of 250 uM.
  • the sample is incubated at 27°C for 1 hour and reaction is by the addition of 40 microliters of 5% trifluoroacetic acid in water.
  • the sample is analyzed by HPLC to quantitate the amounts of the substrate peptide and of the N-terminal and C-terminal cleavage fragments.
  • the percentage cleavage is calculated and expressed as a fraction of the value obtained for an uninhibited control sample.
  • the enzyme used in the assay for HSV-2 consists of the proteolytically active domain of the HSV-2 UL26 homologue protein (amino acid residues 1 to 247).
  • WO 95/06055 (SmithKline Beecham Corp.) describes the HSV-2 protease sequence.
  • the enzyme used in the assay for CMV consists of the proteolytically active domain of the CMV UL80 protein (amino acid residues 1 to 256) with the addition of an amino terminal MGHHHHHHHHSSGHIDDDDK.
  • the polypeptide has cleaved beween A 143 and A 144 (natural UL 80 numbering) to give an active heterodimer.
  • the enzyme used in the assay for VZV consists of the proteolytically active domain of the VZV gene 33 protein (amino acid residues 1 to 237).
  • the compounds of the Examples 1 to 69 showed activity in one or more of the above tests at a concentration of 10uM or luM.
  • the Compounds E22 to E39 showed good activity and Compounds E22, E39, E46, E54 showed preferred activity for HSV-2, Compounds E22, E43, E44, E45, E54, E58 showed preferred activity for CMV and Compounds E22, E27, E46, E51, E54, E58 showed preferred activity for VZV. Quenched fluorescence assay for protease inhibition
  • a quenched fluoresecence based assay is currently used to generate IC 50 data for compounds screened against HSV-2, VZV and CMV proteases.
  • the cleavage of a quenched fluorescent (QF) peptide substrate by the protease yields an increase in measured fluorescence over the time of incubation.
  • the assay currently uses a final volume of 200ul of assay mixture in each well. However, volume additions and dilution steps can be altered to cope with any changes in starting and/or final concentrations for each assay component.
  • the steps described below have been configured to run using a Beckman Biomek 2000 robot. Compounds for screening are made up as stock solutions in 100% DMSO. Four compounds in duplicate are arranged per plate for screening against all three proteases.
  • the compound stock solution, in the first well, is serially diluted 1/1 (v/v) with DMSO to produce a 1000 fold decrease in stock concentration across the plate in 11 points.
  • Eight wells are included containing 100% DMSO only for addition to four control and four blank wells on the reaction plate.
  • the reaction plate is an opaque 96 well plate designed for use with a fluorometric plate reader.
  • Compound/DMSO from the dilution plate are transfered to the reaction plate which already contains assay buffer.
  • the type of assay buffer used depends on which of the proteases is being assesed in the screen. For HSV-2 and VZV proteases this is 50mM hepes/150mM NaCl/lmM EDTA/0.01%PEG
  • protease is stored at -20°C, thawed and stored on ice for ⁇ 1hr.
  • the protease stock is then diluted using the correct buffer to 50X the final concentration needed.
  • the diluted protease stock is added to all but the four wells designed to be used as blanks. Buffer only is used in these wells. The final concentrations are
  • the assay mixture is incubated at 27°C for 15 minutes.
  • Solid QF peptide substrate is resuspended in 10% DMSO/water at 400mM. This is further diluted 1/10 with assay buffer and added to each well of the reaction plate to give the final concentration of 10uM.
  • FQ-7 peptide is used as the substrate for HSV-2 and VZV proteases.
  • FQ-8 peptide is used as the substrate for CMV protease.
  • the plate is read every 30 seconds with a Fluostar SLT fluorometric plate reader using Annelisa software, for 15tnin at 27°C. Ex 355/Em 495nm.
  • the Compounds of the Examples 70 onwards showed activity in one or more of the above tests with an IC 50 value of 15uM or less.
  • Compounds E90, E125, E127, E128, E130, EA-10 showed preferred activity for HSV-2
  • Compounds E90, E116, E117, E118, E188, E191, E204, E205, E206, E207, E208, EB-10 showed preferred activity for CMV
  • Compounds E85, E89, E125, E126, E128, E186, showed preferred activity for VZV.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des dérivés 4H-thiéno[2,3-d][1,3]oxazin-4-one, agissant comme inhibiteurs de la protéase de l'herpèsvirus, à substitution en position 2 par XNH-CHR1-, où X est R4CO, R4 représentant une fraction contenant un ou plusieurs groupes fonctionnels choisis parmi un groupe aromatique ou hétéroaromatique, un groupe alcényle, un groupe alcynyle et R1 représente hydrogène ou une chaîne latérale d'acide aminé.
PCT/EP1997/000367 1996-01-26 1997-01-22 Derives de la thienoxazinone utiles comme agents antiviraux Ceased WO1997027200A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15959/97A AU1595997A (en) 1996-01-26 1997-01-22 Thienoxazinone derivatives useful as antiviral agents

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9601546.6 1996-01-26
GBGB9601546.6A GB9601546D0 (en) 1996-01-26 1996-01-26 Pharmaceuticals
GB9610909.5 1996-05-24
GBGB9610909.5A GB9610909D0 (en) 1996-05-24 1996-05-24 Pharmaceuticals
GBGB9612937.4A GB9612937D0 (en) 1996-06-20 1996-06-20 Pharmaceuticals
GB9612937.4 1996-06-20

Publications (1)

Publication Number Publication Date
WO1997027200A1 true WO1997027200A1 (fr) 1997-07-31

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054192A1 (fr) * 1997-05-29 1998-12-03 Smithkline Beecham P.L.C. Nouveaux derives de thienoxazinone utilises comme agents antiviraux
WO1999024460A2 (fr) 1997-11-05 1999-05-20 Novartis Ag Nitriles de dipeptides
US6353017B1 (en) 1997-11-05 2002-03-05 Novartis Ag Dipeptide nitriles
US6642239B2 (en) 2000-02-10 2003-11-04 Novartis Ag Dipeptide nitrile cathepsin K inhibitors
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
WO2006026619A3 (fr) * 2004-08-30 2006-05-04 Us Health Methodes et compositions ayant trait a l'inhibition de virus utilisant des inhibiteurs de rnase h
US7064122B2 (en) 2001-12-20 2006-06-20 Osi Pharmaceuticals, Inc. Pancreatic lipase inhibitor compounds, their synthesis and use
US7932250B2 (en) 2004-07-01 2011-04-26 Daiichi Sankyo Company, Limited Thienopyrazole derivative having PDE7 inhibitory activity
US10336730B2 (en) 2015-08-05 2019-07-02 Bristol-Myers Squibb Company Substituted glycine derived FXIA inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3681351A (en) * 1970-04-15 1972-08-01 Ian Wellings CERTAIN 5,6,7,8-TETRAHYDRO-5,8-ETHANO-PYRIDINO{8 2,3-b{9 -THIENO{8 5,4-d{9 PYRIMIDINES
FR2401164A1 (fr) * 1977-08-22 1979-03-23 Bristol Myers Co Nouvelles thieno-oxazines et medicament anti-allergique les contenant
US4745116A (en) * 1985-06-25 1988-05-17 Syntex (U.S.A.) Inc. 2-oxy-4H-3,1-benzoxazin-4-ones and related compounds and pharmaceutical use
EP0533951A1 (fr) * 1991-04-10 1993-03-31 Japan Tobacco Inc. Nouveau derive d'oxazinone
WO1994007525A1 (fr) * 1992-09-30 1994-04-14 John Lezdey Agent antiviral
WO1996019482A1 (fr) * 1994-12-22 1996-06-27 Smithkline Beecham Plc Derives de thienoxazinone utilisables comme agents antiviraux

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3681351A (en) * 1970-04-15 1972-08-01 Ian Wellings CERTAIN 5,6,7,8-TETRAHYDRO-5,8-ETHANO-PYRIDINO{8 2,3-b{9 -THIENO{8 5,4-d{9 PYRIMIDINES
FR2401164A1 (fr) * 1977-08-22 1979-03-23 Bristol Myers Co Nouvelles thieno-oxazines et medicament anti-allergique les contenant
US4745116A (en) * 1985-06-25 1988-05-17 Syntex (U.S.A.) Inc. 2-oxy-4H-3,1-benzoxazin-4-ones and related compounds and pharmaceutical use
EP0533951A1 (fr) * 1991-04-10 1993-03-31 Japan Tobacco Inc. Nouveau derive d'oxazinone
WO1994007525A1 (fr) * 1992-09-30 1994-04-14 John Lezdey Agent antiviral
WO1996019482A1 (fr) * 1994-12-22 1996-06-27 Smithkline Beecham Plc Derives de thienoxazinone utilisables comme agents antiviraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KRANTZ ET AL.: "Design and Synthesis of 4H-3,1-Benzoxazin-4-ones ...", J.MED.CHEM., vol. 33, 1990, pages 464 - 479, XP002030653 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054192A1 (fr) * 1997-05-29 1998-12-03 Smithkline Beecham P.L.C. Nouveaux derives de thienoxazinone utilises comme agents antiviraux
WO1999024460A2 (fr) 1997-11-05 1999-05-20 Novartis Ag Nitriles de dipeptides
WO1999024460A3 (fr) * 1997-11-05 1999-09-02 Novartis Ag Nitriles de dipeptides
US6353017B1 (en) 1997-11-05 2002-03-05 Novartis Ag Dipeptide nitriles
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
US7265132B2 (en) 1999-09-13 2007-09-04 Boehringer Ingelheim Pharmaceuticals Inc. Compounds useful as reversible inhibitors of cysteine proteases
US7279472B2 (en) 1999-09-13 2007-10-09 Boehringer Ingelheim Pharmaceuticals Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6982272B2 (en) 1999-09-13 2006-01-03 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US7056915B2 (en) 1999-09-13 2006-06-06 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6642239B2 (en) 2000-02-10 2003-11-04 Novartis Ag Dipeptide nitrile cathepsin K inhibitors
US6858623B2 (en) 2000-09-08 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US7064122B2 (en) 2001-12-20 2006-06-20 Osi Pharmaceuticals, Inc. Pancreatic lipase inhibitor compounds, their synthesis and use
EP2433943A1 (fr) 2004-07-01 2012-03-28 Daiichi Sankyo Company, Limited Dérivés de thiénopyrazole ayant une activité inhibitrice de la PDE7
US7932250B2 (en) 2004-07-01 2011-04-26 Daiichi Sankyo Company, Limited Thienopyrazole derivative having PDE7 inhibitory activity
US8901315B2 (en) 2004-07-01 2014-12-02 Daiichi Sankyo Company, Limited Thienopyrazole derivative having PDE7 inhibitory activity
WO2006026619A3 (fr) * 2004-08-30 2006-05-04 Us Health Methodes et compositions ayant trait a l'inhibition de virus utilisant des inhibiteurs de rnase h
US10336730B2 (en) 2015-08-05 2019-07-02 Bristol-Myers Squibb Company Substituted glycine derived FXIA inhibitors
US10899743B2 (en) 2015-08-05 2021-01-26 Bristol-Myers Squibb Company Substituted glycine derived FXIA inhibitors

Also Published As

Publication number Publication date
AU1595997A (en) 1997-08-20

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