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

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Cited By (6)

Citations (2)

• 1994
  • 1994-12-22 GB GBGB9426021.3A patent/GB9426021D0/en active Pending
• 1995
  • 1995-12-20 WO PCT/EP1995/005154 patent/WO1996019482A1/en not_active Application Discontinuation
  • 1995-12-20 JP JP8519530A patent/JPH11500710A/ja active Pending
  • 1995-12-20 AU AU43475/96A patent/AU4347596A/en not_active Abandoned
  • 1995-12-20 CA CA002208458A patent/CA2208458A1/en not_active Abandoned
  • 1995-12-20 CZ CZ971958A patent/CZ195897A3/cs unknown
  • 1995-12-20 EP EP95942205A patent/EP0799230A1/en not_active Ceased
  • 1995-12-20 PL PL95320889A patent/PL320889A1/xx unknown
  • 1995-12-20 CN CN95197615A patent/CN1175258A/zh active Pending
  • 1995-12-20 ZA ZA9510823A patent/ZA9510823B/xx unknown
  • 1995-12-20 HU HU9701822A patent/HUT77123A/hu unknown
  • 1995-12-20 BR BR9510418A patent/BR9510418A/pt not_active Application Discontinuation
• 1997
  • 1997-06-17 FI FI972585A patent/FI972585A/fi unknown
  • 1997-06-20 NO NO972905A patent/NO972905L/no unknown

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