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WO1996019482A1 - Derives de thienoxazinone utilisables comme agents antiviraux - Google Patents

Derives de thienoxazinone utilisables comme agents antiviraux Download PDF

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Publication number
WO1996019482A1
WO1996019482A1 PCT/EP1995/005154 EP9505154W WO9619482A1 WO 1996019482 A1 WO1996019482 A1 WO 1996019482A1 EP 9505154 W EP9505154 W EP 9505154W WO 9619482 A1 WO9619482 A1 WO 9619482A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
exchangeable
oxazin
benzyloxycarbonyl
thieno
Prior art date
Application number
PCT/EP1995/005154
Other languages
English (en)
Inventor
Richard Lewis Jarvest
Martin John Parratt
Halina Teresa Serafinowska
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to BR9510418A priority Critical patent/BR9510418A/pt
Priority to FI972585A priority patent/FI972585A7/fi
Priority to EP95942205A priority patent/EP0799230A1/fr
Priority to PL95320889A priority patent/PL320889A1/xx
Priority to JP8519530A priority patent/JPH11500710A/ja
Priority to AU43475/96A priority patent/AU4347596A/en
Publication of WO1996019482A1 publication Critical patent/WO1996019482A1/fr
Priority to NO972905A priority patent/NO972905L/no
Priority to MXPA/A/1997/004737A priority patent/MXPA97004737A/xx

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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
    • 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 compounds which are of potential use as antiviral agents. It has now been discovered that certain thienoxazinone derivatives are potentially useful in the treatment of infection caused by herpesviruses, especially herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, and varicella-zoster virus.
  • 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][l,3]oxazin-4-one derivatives which are 2-substituted by
  • substituents in the 5 and 6 positions may be selected from halo,
  • R4CO is an acyl group where values of R4 include aryl, alkyl or aralkyl, or R3 and R2 may be joined to form C2, C3, C4, C5, Cg, C ⁇ , or Cg polymethylene.
  • alkyl or alkyl containing groups include C ⁇ , C2, C3, C4, C5,
  • Cg branched, straight chained or cyclic alkyl, as appropriate.
  • C _a alkyl groups include methyl, ethyl n- and wo-propyl, n-, iso-, sec- and t -butyl.
  • Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C ⁇ . alkyl, C g alkoxy and C ⁇ .g alkoxycarbonyl.
  • Halo includes fluoro, chloro, bromo and iodo.
  • Suitable X moieties are those well known in the art of peptide chemistry.
  • Particular values include aryl, alkanoyl, (aryl)alkoxycarbonyl,
  • the 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.
  • the amino acids may be in the D or L form, preferably the L form.
  • Particular examples of amino acids for Y include alanine, asparagine, valine and similar amino acids.
  • 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 containing amino acid or dipeptide by standard peptide procedures such as: i) formation of an activated ester with a carbodiimide or other coupling reagent and a moiety such as 1-hydroxybenzotriazole, or ii) formation of a mixed anhydride with a reagent such as isobutyl chloroformate and reacting with a 2-aminothiophene 3-carboxylic acid or ester.
  • 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. 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). Pharmaceutically acceptable salts 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, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus.
  • herpesviruses such as herpes simplex types 1 and 2, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus.
  • Other herpesviruses are also of potential interest, such as herpesvirus-6.
  • compositions 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 Pharmacopaeia.
  • 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. No unacceptable toxicological effects are indicated at the above described dosage levels.
  • 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.
  • Standard abbreviations used for the amino acids are the single letter codes.
  • Example 2 (step 1) Ethyl 2-[N-(benzyloxycarbonyI)-L-alaninyI]amino-4-methylthiophene-3- car boxy late
  • Example 7 (step 4) (5)-2-[N-(BenzyloxycarbonyI)-l-aminoethyI]-5-methyl-6-acetamido-4H- thieno[2,3-d][l,3]oxazin-4-one
  • Example 9 (step 1) Ethyl -2-[(N-benzyloxycarbonyl-L-alaninyl)amino]-4-methyI-5-(N- hexanoylamino)thiophene-3-carboxylate
  • reaction mixture was concentrated, the residue was coevaporated with toluene (2 x 5 ml) and purified by column chromatography on silica gel to give thiophene diimides and/or thiophene ureas.
  • the diimides were treated with glacial acetic acid in dichloromethane (1:9, 2 ml) at RT for 45 min- 130 min. The solvent was removed and the residue was coevaporated with toluene (2 x 5 ml).
  • the alkyl ureas were purified by column chromatography on silica gel, eluting with ethyl acetate-hexane or ethyl acetate-dichloromethane mixtures.
  • aryl ureas aryl ureas:
  • Example 24 (step 2) (S)-2-[N-(BenzyIoxycarbonyI)-l-aminoethyl]-5-methyI-6-(N ⁇ -dimethylamino)- 4H-thieno[2,3-d][l,3]oxazin-4-one
  • Example 30 (step 1) Methyl 2-amino-4-ethyl-5-methylthiophene-3-carboxylate
  • 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) with the addition of an amino terminal MGHHHHHHSSA.
  • 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 A143 and A144 (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 results were as follows:
  • the compounds of the Examples showed activity in one or more of the above tests at a concentration of lOuM or luM.
  • the compounds of Examples 1-4, 7-10, 12-18, 21-22, 24-29 and 35 afforded > 50% inhibition of one or more of the proteases at a concentration of 1 uM, the Compounds of Examples 10, 17, 18, 21, 27; 2, 3, 15, 21, 28; and 8, 15, 21, 28; showing preferred activity for HSV-2; CMV; and VZV; respectively.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Dérivés 4H-thiéno (2,3-d)(1,3) oxazin-4-one, de la formule (I), agissant comme inhibiteurs de la protéase de l'herpèsvirus, et substitués par X(Y)NH-CHR1-, où X représente hydrogène ou un groupe inhibiteur, Y représente un acide aminé éventuellement présent, et R1 représente hydrogène ou une chaîne latérale d'acide aminé.
PCT/EP1995/005154 1994-12-22 1995-12-20 Derives de thienoxazinone utilisables comme agents antiviraux WO1996019482A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BR9510418A BR9510418A (pt) 1994-12-22 1995-12-20 Derivados tienoxazinona úteis como agentes antivirais
FI972585A FI972585A7 (fi) 1994-12-22 1995-12-20 Virustenvastaisina aineina käyttökelpoiset tienoksatsinonijohdannaiset
EP95942205A EP0799230A1 (fr) 1994-12-22 1995-12-20 Derives de thienoxazinone utilisables comme agents antiviraux
PL95320889A PL320889A1 (en) 1994-12-22 1995-12-20 Derivatives of thiene oxazinone useful as antiviral agent
JP8519530A JPH11500710A (ja) 1994-12-22 1995-12-20 抗ウイルス剤として有用なチエノキサジノン誘導体
AU43475/96A AU4347596A (en) 1994-12-22 1995-12-20 Thienoxazinone derivatives useful as antiviral agents
NO972905A NO972905L (no) 1994-12-22 1997-06-20 Tienoksasinon-derivater anvendelige som antivirusmidler
MXPA/A/1997/004737A MXPA97004737A (en) 1994-12-22 1997-06-23 Derivatives of tienoxazinone useful as antivira agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9426021.3 1994-12-22
GBGB9426021.3A GB9426021D0 (en) 1994-12-22 1994-12-22 Pharmaceuticals

Publications (1)

Publication Number Publication Date
WO1996019482A1 true WO1996019482A1 (fr) 1996-06-27

Family

ID=10766452

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/005154 WO1996019482A1 (fr) 1994-12-22 1995-12-20 Derives de thienoxazinone utilisables comme agents antiviraux

Country Status (14)

Country Link
EP (1) EP0799230A1 (fr)
JP (1) JPH11500710A (fr)
CN (1) CN1175258A (fr)
AU (1) AU4347596A (fr)
BR (1) BR9510418A (fr)
CA (1) CA2208458A1 (fr)
CZ (1) CZ195897A3 (fr)
FI (1) FI972585A7 (fr)
GB (1) GB9426021D0 (fr)
HU (1) HUT77123A (fr)
NO (1) NO972905L (fr)
PL (1) PL320889A1 (fr)
WO (1) WO1996019482A1 (fr)
ZA (1) ZA9510823B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027200A1 (fr) * 1996-01-26 1997-07-31 Smithkline Beecham Plc Derives de la thienoxazinone utiles comme agents antiviraux
WO1997048707A1 (fr) * 1996-06-20 1997-12-24 Smithkline Beecham Plc Derives de la 4h-3,1-benzoxazin-4-one et analogues utilises comme agents antiviraux
WO1998045298A1 (fr) * 1997-04-10 1998-10-15 Smithkline Beecham Plc Agents antiviraux
WO1998054192A1 (fr) * 1997-05-29 1998-12-03 Smithkline Beecham P.L.C. Nouveaux derives de thienoxazinone utilises comme agents antiviraux
US6514980B1 (en) 1996-01-26 2003-02-04 Novartis International Pharmaceutical Ltd. Nucleoside analogs in combination therapy of herpes simplex infections
US7064122B2 (en) 2001-12-20 2006-06-20 Osi Pharmaceuticals, Inc. Pancreatic lipase inhibitor compounds, their synthesis and use

Citations (2)

* 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

Patent Citations (2)

* 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

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027200A1 (fr) * 1996-01-26 1997-07-31 Smithkline Beecham Plc Derives de la thienoxazinone utiles comme agents antiviraux
US6514980B1 (en) 1996-01-26 2003-02-04 Novartis International Pharmaceutical Ltd. Nucleoside analogs in combination therapy of herpes simplex infections
WO1997048707A1 (fr) * 1996-06-20 1997-12-24 Smithkline Beecham Plc Derives de la 4h-3,1-benzoxazin-4-one et analogues utilises comme agents antiviraux
WO1998045298A1 (fr) * 1997-04-10 1998-10-15 Smithkline Beecham Plc Agents antiviraux
WO1998054192A1 (fr) * 1997-05-29 1998-12-03 Smithkline Beecham P.L.C. Nouveaux derives de thienoxazinone utilises comme agents antiviraux
US7064122B2 (en) 2001-12-20 2006-06-20 Osi Pharmaceuticals, Inc. Pancreatic lipase inhibitor compounds, their synthesis and use

Also Published As

Publication number Publication date
CA2208458A1 (fr) 1996-06-27
AU4347596A (en) 1996-07-10
JPH11500710A (ja) 1999-01-19
CN1175258A (zh) 1998-03-04
FI972585L (fi) 1997-08-19
EP0799230A1 (fr) 1997-10-08
FI972585A0 (fi) 1997-06-17
NO972905D0 (no) 1997-06-20
FI972585A7 (fi) 1997-08-19
ZA9510823B (en) 1996-08-16
CZ195897A3 (cs) 1998-03-18
PL320889A1 (en) 1997-11-10
NO972905L (no) 1997-08-18
HUT77123A (hu) 1998-03-02
GB9426021D0 (en) 1995-02-22
BR9510418A (pt) 1998-05-19
MX9704737A (es) 1997-10-31

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