WO1993001174A1 - Derives de thiazolidine et leur utilisation comme composes antiviraux - Google Patents

Derives de thiazolidine et leur utilisation comme composes antiviraux Download PDF

Info

Publication number
WO1993001174A1
WO1993001174A1 PCT/EP1992/001494 EP9201494W WO9301174A1 WO 1993001174 A1 WO1993001174 A1 WO 1993001174A1 EP 9201494 W EP9201494 W EP 9201494W WO 9301174 A1 WO9301174 A1 WO 9301174A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
amino
hydrogen
carbonyl
group
Prior art date
Application number
PCT/EP1992/001494
Other languages
English (en)
Inventor
John Kitchin
Duncan Stuart Holmes
David Cedric Humber
Richard Storer
Simon Charles Dolan
Michael Menteith Hann
Peter MCMEEKIN
Peter MURRAY-RUST
Binakumari PATEL
Gordon Gad Weingarten
Original Assignee
Glaxo Group 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 GB919114692A external-priority patent/GB9114692D0/en
Priority claimed from GB919114701A external-priority patent/GB9114701D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO1993001174A1 publication Critical patent/WO1993001174A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to therapeutically active thiazolidine derivatives, processes for the manufacture of said compounds, pharmaceutical formulations containing said compounds and the use of said compounds in chemotherapy, more particularly in the therapy of viral infections.
  • Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Their presence has been associated with a wide range of diseases in humans and animals, and they are believed to be the causative agents in pathological states associated with many viruses including human immunodeficiency virus (HIV-1, HIV-2), the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • HIV-1, HIV-2 human immunodeficiency virus
  • HIV-2 the etiological agent of the complex disease that includes progressive destruction of the immune system
  • AIDS progressive destruction of the immune system
  • a common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function.
  • the proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host cells and is essential to the life cycle of the retrovirus. It has been demonstrated that retroviruses which lack the protease or contain a mutated form of it lack infectivity [cf. S. Crawford et al., J. Virol., 53, 899-907 (1985)]. Inhibition of retroviral protease, therefore, presents a method of therapy for retroviral disease.
  • the compounds of the present invention inhibit proteases of retroviral origin and are therefore useful in the treatment of infections associated with retroviruses, especially AIDS and related conditions such as AIDS related complex (ARC) and lymphadenopathy.
  • AIDS AIDS related complex
  • lymphadenopathy AIDS related complex
  • the present invention provides compounds of formula
  • R 1 is hydrogen, C 1-4 alkyl or CH 2 C 1-3 alkyl where the C 1-3 alkyl portion is substituted by OH;
  • R 3 is hydrogen, C 1-6 alkyl, COOR 12 (where R 12 is hydrogen, C 1-6 alkyl or
  • Ar C 1-4 alkyl or CONR 13 R 14 [where R 13 is hydrogen or C 1-4 alkyl and R 14 is hydrogen, OH, aryl, heteroaryl, ArC 1-4 alkyl, (wherein the C 1-4 alkyl portion is optionally substituted by hydroxymethyl), HetC 1-4 alkyl, C 3-8 cycloalkyl,
  • R 17 and R 18 are each independently hydrogen, C 1-4 alkyl or aryl or together with the nitrogen atom to which they are attached form a saturated heterocyclic amino group), CHArCO 2 R 19 , CHHetCO 2 R 20 (where R 19 and R 20 are each independently hydrogen or C 1-6 alkyl) or Chalky! optionally substituted by OH, or R 13 and R 14 together with the nitrogen atom to which they are attached form a saturated heterocyclic amino group];
  • R is hydrogen, hydroxy, or acetoxy
  • A represents either a group CHR 21 CHR 22 OH or a group
  • R 21 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl C 1-4 alkyl or Ar C 1-4 alkyl
  • R 22 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkylC 1-4 alkyI, ArC 1-4 alkyl, CHR 24 CONR 25 R 26 (where R 24 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl C 1-4 alkyl or Ar C 1-4 alkyl, R 25 is hydrogen or methyl and R 26 is hydrogen, C 1-6 alkyl optionally substitued by one or two hydroxyl groups, aryl, heteroaryl, C 3-8 cycloalkyl C 1-4 alkyl, Ar C 1-4 alkyl wherein the C 1-4 alkyl portion is optionally substituted by hydroxymethyl, or HetC 1-4 alkyl) or CHR 24 NHCOR 27 (where R 27 is C 1-6 alkyl, C 3-8 cycloalkyl C 1-4 alkyl or a Ar CHR
  • X is a group
  • Y is a methyl group and Z is a C 5 or C 6 cycloalkylmethyl group or Y and Z together represent a trimethylene or tetramethyiene group in which one of the -CH 2 - groups is optionally replaced by -O-, -S- or -NR - (where R 34 is hydrogen, Chalky!, Ar C 1-4 alkyl, COR 35 , CO 2 R 35 or CONHR 35 where R 35 is C 1-6 alkyl, aryl, ArC 1-4 alkyl or C 3 - 8 cycloalkylC 1-4 alkyl) and one or more of the -CH 2 - groups is optionally substituted by a C 1-6 alkyl, C 1-6 alkoxy, aryl, ArC 1-4 alkyl, ArC 1-4 alkoxy or heteroaryl group or by two C 1-6 alkyl groups, or Y and Z together represent a trimethylene or tetramethyiene group fused to a benzene ring
  • Suitable physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed with organic or inorganic acids [for example, hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates] and inorganic base salts such as alkali metal salts (for example sodium salts).
  • the solvates may, for example, be hydrates.
  • the term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
  • the term 'C 3-8 cycloalkyl' as a group or part of a group includes, for example, cyclopropyl, cyclopentyl and cyclohexyl.
  • heteroaryl' and 'Het' as a group or part of a group respectively, mean an optionally fused 5- or 6-membered heterocyclic group containing one or more heteroatoms selected from S, N and O and optionally substituted by one or more suitable substituents.
  • Suitable substituents referred to above within the definitions of 'aryl', 'Ar', 'heteroaryl' and 'Het' include halogen, C 1-6 alkyl, a group (CH 2 ) r R 36 [where r is zero, 1, 2, 3 or 4 and R 36 is selected from OH, C 1-3 alkoxy, CF 3 , CN, NO 2 , heteroaryl, CO 2 R 37 (where R 37 is hydrogen or C 1-6 alkyl), CONR 38 R 39 , SO 2 NR 38 R 39 or NR 38 R 39 (where R 38 and R 39 each independently represent hydrogen, C 1-4 alkyl or phenyl or together with the nitrogen atom to which they are attached form a saturated heterocyclic amino group)], phenyl, phenoxy and phenylC 1-4 alkyl (such phenyl, phenoxy and phenylC 1-4 alkyl substituents themselves optionally substituted in the phenyl ring by halogen, C
  • heterocyclic ring systems include thienyl, furyl, pyridyl, pyrrolyl, isothiazolyl, thiadiazolyl, oxazolyl, benzothienyl, benzofuryl, indolyl, quinolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, benzoxazolyl and benzimidazolyl.
  • the term 'halogen' means fluorine, chlorine, bromine or iodine.
  • the term 'saturated heterocyclic amino group' means a nitrogen linked cyclic amine group having 5, 6, 7 or 8 ring members and optionally containing in the ring -O- or -NR 4 - (where R 40 is hydrogen, C 1-4 alkyl, aryl or ArC 1-4 alkyl).
  • the saturated heterocyclic amino group may for example have 5, 6 or 7 ring members and includes as examples pyrrolidino, piperidino, morpholino, piperazino, N-phenylpiperazino, homomorpholino and hexamethyleneimino.
  • groups 'aryl' and 'Ar' include phenyl or phenyl substituted by F, Cl, di-Cl, OH, methyl, methoxy, CF 3 , NO 2 , CH 2 OH, CO 2 H, CO 2 Bu-t, (CH 2 ) r NR 38 R 39 (where r is zero or 1 and R 38 and R 39 each independently represent hydrogen or C 1-4 alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 membered saturated heterocyclic amino group), phenyl or benzyl, and naphthyl or naphthyl substituted by ethoxy.
  • X specifically represents a group selected from -CH(CH 2 OH)CH 2 -,- CH 2 CH(CH 2 OH)-, - CH 2 CH (OH) CH 2 -, - CH 2 CH(CH 2 OH) CH 2 -, - CH 2 CH(OH)CH 2 CH 2 -, -CH 2 CH 2 CH(OH)CH 2 - and -CH 2 CH(OH)CH(OH)CH 2 -.
  • R 1 preferably represents a hydrogen atom or a methyl group.
  • R 2 preferably represents a group selected from COAr (where Ar is biphenyl), COCH 2 R 5 (where R 5 is C 1-6 alkyl, for example C 1-4 alkyl such as isopropyl; aryl, for example phenyl optionally substituted by chlorine; heteroaryl, for example pyridyl; aryloxy, for example phenoxy; or Ar C 1-4 alkyl, for example ArCH 2 such as benzyl) or COR 6 (where R 6 is cyclopropyl substituted by phenyl).
  • COCH 2 OPh, CO(CH 2 ) 2 Ph or COCH 2 Pr-i are particularly preferred.
  • R 3 preferably represents a group CONR 13 R 14 where R 13 and R 14 are as defined hereinabove.
  • R 13 is hydrogen and R 14 is a group selected from ArC 1-4 alkyl (e.g. ArC 1-2 alkyl where Ar is phenyl optionally substituted by CF 3 , methoxy, NR 38 R 39 where R 38 and R 39 each independently represent methyl or ethyl or together with the nitrogen atom to which they are attached form a pyrrolidino group, Cl, di-Cl or CO 2 R 37 where R 37 is hydrogen or C 1-4 alkyl e.g. t-butyl), HetC 1-4 aIkyl (e.g.
  • R 3 may particularly represent CONHCH 2 Ph, CONHCH 2 CH 3 , CONHCH 2 CH 2 Ph, CONMe 2 , , ,
  • R 22 preferably represents a group CHR 24 CONR 25 R 26 where R 24 , R 25 and
  • R 26 are as defined previously.
  • -NCHR 21 CHR 22 OH may particularly represent a group -NHCHR 21 CH(OH)CH 2 CONHR 26 where R 21 and R 26 are as defined previously.
  • R 21 represents ArC 1-4 alkyl (e.g. benzyl) and R 26 represents ArC 1 -4 alkyl (e.g. benzyl) or HetC 1-4 alkyl (e.g. benzimidazol-2-ylmethyl) are preferred.
  • Examples of ring systems represented by N Y-CHZ include thiazolidine, piperazine, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and decahydroisoquinoline.
  • a preferred group of compounds of the present invention are compounds of formula (I) in which A represents a group
  • a particularly preferred group of compounds of the invention are those of formula (la)
  • R 1 -R 3 ,R 23 and X are as defined above, and physiologically acceptable salts and solvates thereof.
  • the group X as referred to in formulae (I) and (la) above may preferably represent -CH 2 CH(OH)CH 2 -.
  • R 23 as referred to in formulae (I) and (la) above may preferably represent NR 28 R 29 , especially where R 28 is hydrogen and R 29 is C 1-6 alkyl (e.g. t-butyl).
  • Particularly preferred compounds according to the invention are:
  • the compounds of the invention possess antiviral activity.
  • compounds of the invention are effective in inhibiting the replication of retroviruses, including human retroviruses such as human immunodeficiency viruses (HIV's), the causative agents of AIDS.
  • retroviruses including human retroviruses such as human immunodeficiency viruses (HIV's), the causative agents of AIDS.
  • HIV's human immunodeficiency viruses
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent, in particular as an antiviral agent, for example in the treatment of retroviral infections.
  • a method for the treatment of a viral infection in particular an infection caused by a retrovirus such as HIV, in a mammal including man comprising administration of a therapeutical ly effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • the compounds of the invention are also potentially useful in the treatment of AIDS related conditions such as AIDS-related complex (ARC), progressive generalised lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia or tropical paraparesis), anti-HIV antibody positive and HIV-positive conditions, Kaposi's sarcoma and thrombocytopenia purpura.
  • AIDS related conditions such as AIDS-related complex (ARC), progressive generalised lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia or tropical paraparesis), anti-HIV antibody positive and HIV-positive conditions, Kaposi's sarcoma and thrombocytopenia purpura.
  • the compounds of the invention are also useful in the prevention of progression to clinical illness of individuals who are anti-HIV antibody or HIV-antigen positive and in prophylaxis following exposure to HIV.
  • the compounds of formula (I) or the physiologically acceptable salts or solvates thereof may also be used for the prevention of viral contamination of physiological fluids such as blood or semen in vitro.
  • protease inhibiting properties of the compounds of the present invention can be demonstrated in vitro by their ability to inhibit the hydrolysis of an appropriate peptide substrate by HIV protease according to methods generally known in the art.
  • antiviral activity of compounds of the invention may be demonstrated in vitro by their effect on cells infected with HIV-RF according to the following procedure :-
  • C8166 cells were infected with HIV-1 (strain RF) at a moi of 1 ⁇ 10 -3 infectious units/cell. Aliquots of 10 5 cells were added to each well of 24-well plates containing serial dilutions of test compounds at final concentrations of 50 ⁇ g/ml to 0.05 ⁇ g/ml in RPMI 1640 growth medium. Untreated infected cells and untreated uninfected cells were also included as controls. The plates were incubated at 37 C/5% carbon dioxide for 3-4 days in humidified containers. The cells were examined daily for evidence of HIV-1 induced syncytium formation. The syncytia were quantified by reference to the untreated infected controls and the dose of compound required to reduce the cytopathic effect by 50% (EC 50 ) was calculated.
  • Virus injections were prepared according to the inhibition of syncytium formation assay hereinabove. Supernatant fluids cleaved by centrifugation were assayed for p24 antigen using an ELISA kit. The synthesis of p24 core antigen was quantified by reference to the untreated infected controls and the dose of compound required to reduce the cytopathic effect by 50%. (EC 50 ) was calculated.
  • a suitable dose will be in the range of from about 1 to about 750mg/kg of bodyweight per day, such as about 3 to about 120mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90mg/kg/day, most preferably in the range of 15 to 60mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the compound is conveniently administered in unit dosage form; for example containing 10 to 1500mg, conveniently 20 to 1000mg, most conveniently 50 to 700mg of active ingredient per unit dosage form.
  • the active ingredient should be adminsitered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 ⁇ M, preferably about 2 to 50 ⁇ M, most preferably about 3 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 100mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15mg/kg of the active ingredient.
  • a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
  • the compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, prefilled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one more more dispersing agents, solubilising agents or suspending agents. Liquid sprays are conveniently delivered from pressurised packs.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebuliser or a pressurised pack or other convenient means of delivering an aerosol spray.
  • Pressurised packs may comprise a s Menb le propellant s uch as d ich lorod ifluoromethane , trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • compositions according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.
  • the compounds of the invention may also be used in combination with other therapeutic agents for example other antiinfective agents.
  • the compounds of the invention may be employed together with known antiviral agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable derivative thereof together with another therapeutically active agent, in particular an antiviral agent.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention.
  • Suitable therapeutic agents for use in such combinations include (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yI)-(1H)-pyrimidin-2-one (3TC), 3'-azido-3'-deoxythymidine (AZT), ribavirin, 3'-azido-2',3'-dideoxyuridine, acyclic nucleosides such as acyclovir, interferons such as ⁇ -interferon, renal excretion inhibitors such as probenicid, inhibitors of retroviral protease, 2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine, 2',3'-dideoxyadenosine 2',3'-dideoxyinosine and 2',3'-dideoxy-2',3'- didehydrothymidine, non-nucleoside reverse transcriptase (RT) inhibitors
  • IL2 interleukin II
  • GM-CSF granulocyte macrophage colony stimulating factor
  • erythropoetin erythropoetin and ampligen.
  • IL2 interleukin II
  • GM-CSF granulocyte macrophage colony stimulating factor
  • erythropoetin erythropoetin and ampligen.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the reaction is conveniently carried out in a suitable solvent such as water, a halogenated hydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran), an alcohol (e.g. ethanol or methanol) or a water-miscible solvent such as dimethylformamide or dimethylsulphoxide or a suitable mixture of such solvents at about room temperature, optionally in the presence of a suitable base such as an amine (eg diisopropylethylamine).
  • a suitable solvent such as water, a halogenated hydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran), an alcohol (e.g. ethanol or methanol) or a water-miscible solvent such as dimethylformamide or dimethylsulphoxide or a suitable mixture of such solvents at about room temperature, optionally in the presence of a suitable base such as an amine (eg diisopropylethy
  • R 12 is C 1-6 alkyl or ArC 1-4 alkyl the reaction is effected using an alcohol R 12 OH or an alkali metal alkoxide (e.g. NaOR 12 ).
  • R 12 is hydrogen the reaction is conveniently effected using a hydroxide such as sodium hydroxide.
  • the coupling may conveniently be effected in the presence of a coupling agent such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in the presence of a base such as N,N-diisopropylethylamine and in a suitable solvent (e.g. dimethylformamide) or N,N'-dicyclohexylcarbodiimide optionally in the presence of 1-hydroxybenzotriazole (or its hydrate) and in a suitable solvent such as a halogenated hydrocarbon (e.g.
  • a coupling agent such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
  • a base such as N,N-diisopropylethylamine
  • a suitable solvent e.g. dimethylformamide
  • dichloromethane or, more particularly, an ether (e.g. tetrahydrofuran). Under these conditions the reaction may conveniently be carried out at about room temperature.
  • the coupling may alternatively be effected in the presence of ethyl chloroformate and N-ethylpiperidine in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane), conveniently at a temperature in the range of -20°C to +50°C.
  • a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane)
  • compounds of formula (I) in which R 2 represents an acyl or sulphonyl group may be prepared from the corresponding primary amine of formula (I) using conventional acylating or sulphonylating means.
  • a group CO 2 CH 2 Ar or CO 2 CH 2 Het may be introduced by reacting the amine with a haloformate (e.g. a chloroformate ClCO 2 CH 2 Ar or ClCO 2 CH 2 Het) in a solvent such as water, preferably in the presence of a base such as an alkali metal carbonate (e.g. sodium carbonate).
  • the amine may be regenerated from the so-formed grouping by treatment with an acid such as hydrobromic acid in acetic acid, conveniently in a solvent such as a halogenated hydrocabon (e.g. dichloromethane).
  • the desired group may be introduced by reacting the amine with an anhydride in the presence of a suitable base such as an organic base (e.g. pyridine).
  • an appropriate sulphonyl halide e.g. a sulphonyl chloride
  • a solvent such as a halogenated hydrocarbon (e.g. dichloromethane)
  • a suitable base such as an organic base (e.g. triethylamine).
  • compounds of formula (I) in which R 3 contains a carboxyl group may be prepared from the corresponding carboxylic acid ester of formula (I) using conventional means.
  • conversion of a t-butyl ester to be corresponding acid may conveniently be carried out by treating the ester with an acid such as hydrobromic acid in acetic acid, conveniently in a solvent such as a halogenated hydrocarbon (e.g. dichloromethane).
  • Compounds of formulae (III) in which R 3 is hydrogen and compounds of formulae (IV) and (V) are either known compounds or may be prepared from the known compounds of formulae (III), (IV) and (V) using conventional means.
  • compounds of formula (IV) may be prepared according to the procedures illustrated in the Examples hereinafter.
  • hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphe ⁇ ylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl e.g. methyl, t-butyl or methoxymethyl
  • aralkyl e.g. benzyl, diphe ⁇ ylmethyl or triphenylmethyl
  • heterocyclic groups such as tetrahydropyranyl
  • acyl e.g. acetyl or benzoyl
  • silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions.
  • Aralkyi groups such as triphenylmethyl may similarly be removed by solvolysis, e.g. by hydrolysis under acidic conditions.
  • Aralkyi groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as palladium-on-charcoal.
  • Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
  • Carboxyl protecting groups may conveniently be protected using appropriate hydroxyl protecting groups above with deprotection effected according to the methods described above.
  • Particular isomers of formula (I) may either be prepared from starting materials having the desired stereochemistry or by epimerisation at an appropriate stage in the synthesis of the required compounds of formula (I). Epimerisation maybe effected using conventional means, for example by treatment with an appropriate acid.
  • interconversions as outlined in process (C) above may also be carried out on appropriate intermediates such that the desired R 2 and R 3 groupings are introduced prior to the final step conversion reaction.
  • Physiologically acceptable acid addition salts of the compounds of formula (I) may be prepared by reacting a compound of formula (I) in the form of the free base with an appropriate acid optionally in the presence of a suitable solvent such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or isopropanol).
  • a suitable solvent such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or isopropanol).
  • Inorganic basic salts may be prepared by reacting the free base of a compound of formula (I) with a suitable base e.g. an alkoxide such as sodium methoxide optionally in the presence of a solvent (e.g. an alcohol such as methanol).
  • a suitable base e.g. an alkoxide such as sodium methoxide
  • a solvent e.g. an alcohol such as methanol
  • Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compounds of formula (I) using conventional methods.
  • Solvates e.g. hydrates of a compound of formula (I) may be formed during the work-up procedure of one of the aforementioned process steps.
  • Triethy lam ine (3.75m l) was add ed to a sus pension of p- dimethylaminobenzylamine dihydrochloride (3.0g) in dichloromethane (60ml), followed by penicillin G N-ethyl piperidine salt (3.01g).
  • the reaction mixture was stirred at room temperature for 18h and the solvent then evaporated in vacuo to give a solid.
  • the solid was dissolved in a mixture of ethyl acetate (350ml) and water (150ml), and 2N phosphoric acid added to pH3.0.
  • N-Benzyloxycarbonyl-D-phenylalanine (1.5g) in tetrahydrofuran (12.6ml) was stirred at -15o and triethylamine (0.73ml) and ethyl chloroformate (0.5ml) added.
  • the white precipitate was filtered and the filtrate was added to an ethereal solution of diazomethane [30ml; prepared from diazald (1.4g)] in a salt-ice bath. After stirring for 30min, the yellow solution was set aside to warm to room temperature overnight. Then a stream of hydrogen chloride gas was bubbled through the solution until the colour was discharged.
  • Trifluoroacetic acid (15ml) and triethylsilane (1.5ml) were added to a solution of Intermediate 44 in chloroform (15ml) and the mixture stirred 21hr.
  • the solvent was evaporated in vacuo and the residue then purified by silica gel column chromatography using chloroform/methanol/water (180:20:1) as eluant to give the title compound (1.37g), 1 H n.m.r.
  • reaction mixture was concentrated to an oil and purified by column chromatography on silica gel (Merck 9385, 20g) using a chloroform:methanol (100:1 ⁇ 20:1) gradient elution to yield the title compound (407mg) as a 1:1 mixture of diastereoisomers, 1 H n.m.r (DMSO-d 6 ) ⁇ 1.25 (9H), 1.35 (9H), 1.5-1.8 (3H), 1.9-2.6 (3H), 2.6-3.7 (6H), 4.72 (0.5H), 4.94 (0.5H), 6.70 (1H), 7.38 (0.5H) and 7.68 (0.5H).
  • DL-Penicillamine acetone adduct hydrochloride monohydrate (4.85g) was dissolved in dimethylformamide (100ml) and diisopropylethylamine (5.1g), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (6.4g) and tert-butylamine (2.1ml) added. The solution was stirred for 2h at room temperature. Water (300ml) was then added and the solution extracted with ethyl acetate (2 ⁇ 150ml).
  • the salt was dissolved in dimethylformamide (4ml) and diisopropylethylamine (400 ⁇ l), [2R-[2 ⁇ (R*),4 ⁇ ]]-5,5-dimethyl-2-[2-oxo-1-[(phenylacetyl)amino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.19g) added. After stirring at room temperature for 16h the reaction mixture was partitioned between ethyl acetate and water.
  • the amine hydrochloride was dissolved in dimethylformamide (5ml) and diisopropylethylamine (131 ⁇ l), [2R-[2 ⁇ (R*),40]]-5,5-dimethyl-2-[2-oxo-1-[phenylacetyl)amino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (0.2g) and 2-(1H-benzotriazol-1- yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.15g) added. After stirring at room temperature for 18h the reaction mixture was partitioned between ethyl acetate and water.
  • the amine hydrochloride was dissolved in dimethylformamide (5ml) and diisopropylethylamine (193 ⁇ l), [2R-[2 ⁇ (R*),4 ⁇ ]]-5,5-dimethyl-2-[2-oxo-1-[(phenylacetyl)amino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (0.24g) and 2-(1H-benzotriazol-1-yl)-l,1,3,3-tetramethyluronium tetrafluoroborate (0.16g) added. After stirring at room temperature for 18h the reaction mixture was partitioned between ethyl acetate and water.
  • the aqueous layer was extracted with ethyl acetate and the combined organic layers washed with IN-hydrochloric acid, saturated sodium hydrogen carbonate solution and brine.
  • the acid extract was basified to pH8 with potassium hydrogen carbonate to give a white solid which was removed by filtration.
  • the salt was dissolved in dimethylformamide (5ml) and diisopropylethylamine (183 ⁇ l), [2R-[2 ⁇ (R *),4 ⁇ ]]-5,5-dimethyl-2- [2-oxo- 1 - [(pheny lacetyl)amino]-2- [(phenylmethyl)amino]ethyl]-4-thiazoIidinecarboxylic acid (232mg) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (156mg)were added sequentially. After stirring at room temperature for 16h the reaction mixture was partitioned between ethyl acetate and water.
  • the salt was dissolved in dimethylformamide (5ml) and diisopropylethylamine (130 ⁇ l), [2R-[2 ⁇ (R * ),4 ⁇ ]]-5,5,dimethy l-2- [2-oxo- 1 - [(pheny lace ty l)amino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (165mg) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (110mg) were added sequentially. After stirring at room temperature for 16h the reaction mixture was partitioned between ethyl acetate and water.
  • the salt was dissoved in dimethylformamide (5ml) and diisopropylethylamine (189 ⁇ l), [2R-[2 ⁇ (R *),40]]-5,5-dimethyl-2- [2-oxo- 1 - [(phenylacetyl)amino]-2-[(phenyImethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (240mg) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (160mg) were added sequentially. After stirring at room temperature for 17h the reaction mixture was partitioned between ethyl acetate and water.
  • the salt was dissolved in dimethylformamide (5ml) and diisopropylethylamine (156 ⁇ l), [2R-[2 ⁇ (R *),40]]-5, 5-dimethyl-2- [2-oxo- l - [(phenylacetyl)amino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (198mg) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (132mg) were added sequentially. After stirring at room temperature for 17h the reaction mixture was partitioned between ethyl acetate and water.
  • the salt was dissolved in dimethylformamide (5ml) and diisopropylethylamine (145 ⁇ l), [2R-[2 ⁇ (R * ),4 ⁇ ]] -5,5-dim ethy l-2- [2-oxo- 1 - [(pheny lacetyl)amino]-2- [(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (235mg) and 2-(1H- benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (188mg) were added sequentially.
  • the salt was dissolved in dimethylformamide (10ml) and diisopropylamine (221 ⁇ l), [2R-[2 ⁇ (R * ),4 ⁇ ]]-5, 5-dim ethyl-2- [2-oxo- 1 - [(phen y lacetyl)am ino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (267mg) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyiuronium tetrafluoroborate (213mg) were added. After stirring at room temperature for 1h the reaction mixture was partitioned between ethyl acetate and water.
  • the salt was dissolved in dimethylformamide (5ml) and diisopropylethylamine (220 ⁇ l), [2R-[2 ⁇ (R*),4 ⁇ ]]-5,5-dimethyl-2-[2-oxo-1- [(phenylacetyl)amino]-2-[(phenylmethyl)amino]ethyl]-4-thiazolidinecarboxylic acid (180mg) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (144mg) were added. After stirring at room temperature for 2h the reaction mixture was partitioned between ethyl acetate and water.
  • Example 23 (204mg) in dichloromethane (8ml) was stirred at room temperature with trifluoroacetic acid (4ml) for 35min. The reaction solution was poured into a mixture of ethyl acetate (50ml) and saturated aqueous sodium hydrogen carbonate and then the organic phase was separated, dried and evaporated to give the title compound (158mg) as a white foam, [ ⁇ ] D 19 -19.8o (c 0.52,DMSO), 1 H n.m.r.
  • n-Heptylamine (0.165ml) was added to a solution of Intermediate 35 (0.35g) in dichloromethane (5ml) and the mixture stirred at room temperature for 17h. The solvent was then evaporated in vacuo and the residue purified by silica gel column chomatography using chloroform/methanol (50:1) as eluant to afford the title compound (65mg), m.p.98-103o, [ ⁇ ] D 23 -5.6o (c 0.98, methanol), 1 H n.m.r.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés répondant à la formule (I), dans laquelle R1 représente hydrogène, alkyle ou CH¿2?alkyle où la partie alkyle est substituée par OH; A représente soit un groupe CHR?21CHR22¿OH ou un groupe (II), où R21 représente hydrogène, alkyle, cycloalkylalkyle ou aralkyle, R22 représente hydrogène, alkyle, cycloalkylalkyle, aralkyle, CHR?24CONR25R26 (où R24¿ représente hydrogène, alkyle, cycloalkylalkyle ou aralkyle, R25 représente hydrogène ou méthyle et R26 représente hydrogène, alkyle éventuellement substitué par un ou deux groupes hydroxyle, aryle, hétéroaryle, cycloalkylalkyle, aralkyle où la partie alkyle est éventuellement substituée par hydroxyméthyle, ou hétalkyle) ou CHR?24NHCOR27 (où R27¿ représente alkyle, cycloalkylalkyle ou aralkyle), R23 représente alcoxy ou NR?28R29 (où R28¿ représente hydrogène ou méthyle et R29 représente hydrogène, alkyle, aryle, aralkyle ou cycloalkylalkyle); X représente un groupe -CHR?30(CHR31)¿r(CHR32)sCHR?32- où R30 et R33¿ représentent hydrogène, r vaut 1, s vaut 0 et R31 représente hydroxyle ou hydroxyméthyle, ou R?30 et R33¿ représentent hydrogène, r et s valent 1 et R?31 et R32¿ représentent chacun hydrogène ou hydroxyle à condition que R31 et/ou R32 représente hydroxyle, que R?30 ou R33¿ représente hydrogène tandis que l'autre représente hydroxyméthyle et que r et s valent 0. Ces composés sont utilisés en chimiothérapie, notamment pour le traitement des infections virales.
PCT/EP1992/001494 1991-07-08 1992-07-03 Derives de thiazolidine et leur utilisation comme composes antiviraux WO1993001174A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9114692.8 1991-07-08
GB919114692A GB9114692D0 (en) 1991-07-08 1991-07-08 Chemical compounds
GB919114701A GB9114701D0 (en) 1991-07-08 1991-07-08 Chemical compounds
GB9114701.7 1991-07-08

Publications (1)

Publication Number Publication Date
WO1993001174A1 true WO1993001174A1 (fr) 1993-01-21

Family

ID=26299200

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001494 WO1993001174A1 (fr) 1991-07-08 1992-07-03 Derives de thiazolidine et leur utilisation comme composes antiviraux

Country Status (2)

Country Link
AU (1) AU2228992A (fr)
WO (1) WO1993001174A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5539122A (en) * 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5541334A (en) * 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5587481A (en) * 1996-02-20 1996-12-24 The Monsanto Company Preparation of (S)-decahydroisoquinoline-3-carboxylic acid t-butylamide
US5663168A (en) * 1993-05-17 1997-09-02 Ciba-Geigy Corporation Use of compositions for combating tumour diseases
WO1997034891A1 (fr) * 1996-03-20 1997-09-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) 1,3-thiazolidin-4-ones et 1,3-thiazolidines substituees, procede d'obtention de ces composes et leurs utilisations comme medicaments
US5886036A (en) * 1992-12-29 1999-03-23 Abbott Laboratories Retroviral protease inhibiting compounds
US6833453B2 (en) 2000-10-17 2004-12-21 Pharmacia & Upjohn Company Methods of producing oxazolidinone compounds
US8906900B2 (en) 2012-12-21 2014-12-09 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8940726B2 (en) 2012-12-21 2015-01-27 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8993555B2 (en) 2012-12-21 2015-03-31 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9221794B2 (en) 2012-12-21 2015-12-29 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365555B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10653693B2 (en) 2014-08-04 2020-05-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346847A2 (fr) * 1988-06-13 1989-12-20 F. Hoffmann-La Roche Ag Dérivés d'amminoacides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346847A2 (fr) * 1988-06-13 1989-12-20 F. Hoffmann-La Roche Ag Dérivés d'amminoacides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, vol. 33, no. 10, October 1990, (Washington, DC, US), R.B. GAMMILL et al.: "Structure-based, C2 symmetrie inhibitors of HIV protease", pages 2687-2689 *
Journal of Medicinal Chemistry, vol. 33, no. 5, May 1990, (Washington, DC, US), D.H. RICH et al.: "Hydroxyethylamine analogues of the p17/p24 substrate cleavage site are tight-binding inhibitors of HIV protease", pages 1285-1288 *

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5597928A (en) * 1989-05-23 1997-01-28 Abbott Laboratories Retroviral protease inhibiting compounds
US5539122A (en) * 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5541334A (en) * 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5552558A (en) * 1989-05-23 1996-09-03 Abbott Laboratories Retroviral protease inhibiting compounds
US5565418A (en) * 1989-05-23 1996-10-15 Abbott Laboratories Retroviral protease inhibiting compounds
US5583233A (en) * 1989-05-23 1996-12-10 Abbott Laboratories Retroviral protease inhibiting compounds
US5583232A (en) * 1989-05-23 1996-12-10 Abbott Laboratories Retroviral protease inhibiting compounds
US5696270A (en) * 1989-05-23 1997-12-09 Abbott Laboratories Intermediate for making retroviral protease inhibiting compounds
US5679797A (en) * 1989-05-23 1997-10-21 Abbott Laboratories Retroviral protease inhibiting compounds
US5541206A (en) * 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5591860A (en) * 1989-05-23 1997-01-07 Abbott Laboratories Retroviral protease inhibiting compounds
US5608072A (en) * 1989-05-23 1997-03-04 Abbott Laboratories Retroviral protease inhibiting compounds
US5616720A (en) * 1989-05-23 1997-04-01 Abbott Laboratories Retroviral protease inhibiting compounds
US5625072A (en) * 1989-05-23 1997-04-29 Abbott Laboratories Retroviral protease inhibiting compounds
US5659044A (en) * 1989-05-23 1997-08-19 Abbott Laboratories Retroviral protease inhibiting compounds
US5659045A (en) * 1989-05-23 1997-08-19 Abbott Laboratories Retroviral protease inhibiting compounds
US6531610B1 (en) 1989-05-23 2003-03-11 Abbott Laboratories Retroviral protease inhibiting compounds
US5597927A (en) * 1989-05-23 1997-01-28 Abbott Laboratories Retroviral protease inhibiting compounds
US5892052A (en) * 1989-05-23 1999-04-06 Abbott Labortories Process for making retroviral protease inhibiting compounds
US6667404B2 (en) 1991-08-15 2003-12-23 Abbott Laboratories Retroviral protease inhibiting compounds
US6017928A (en) * 1992-12-29 2000-01-25 Abbott Laboratories Retroviral protease inhibiting compounds
US5886036A (en) * 1992-12-29 1999-03-23 Abbott Laboratories Retroviral protease inhibiting compounds
US6150530A (en) * 1992-12-29 2000-11-21 Abbott Laboratories Retroviral protease inhibiting compounds
US5663168A (en) * 1993-05-17 1997-09-02 Ciba-Geigy Corporation Use of compositions for combating tumour diseases
US5587481A (en) * 1996-02-20 1996-12-24 The Monsanto Company Preparation of (S)-decahydroisoquinoline-3-carboxylic acid t-butylamide
FR2746396A1 (fr) * 1996-03-20 1997-09-26 Inst Nat Sante Rech Med 1,3-thiazolidin-4-ones et 1,3-thiazolidines substituees, procede d'obtention de ces composes et leurs utilisations comme medicaments
WO1997034891A1 (fr) * 1996-03-20 1997-09-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) 1,3-thiazolidin-4-ones et 1,3-thiazolidines substituees, procede d'obtention de ces composes et leurs utilisations comme medicaments
US6833453B2 (en) 2000-10-17 2004-12-21 Pharmacia & Upjohn Company Methods of producing oxazolidinone compounds
US9388173B2 (en) 2012-12-21 2016-07-12 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9732072B2 (en) 2012-12-21 2017-08-15 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8993555B2 (en) 2012-12-21 2015-03-31 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9221794B2 (en) 2012-12-21 2015-12-29 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9266836B2 (en) 2012-12-21 2016-02-23 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365555B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365519B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8906900B2 (en) 2012-12-21 2014-12-09 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9604930B2 (en) 2012-12-21 2017-03-28 Epizyme, Inc. Tetrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof
US9611257B2 (en) 2012-12-21 2017-04-04 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9675614B2 (en) 2012-12-21 2017-06-13 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8940726B2 (en) 2012-12-21 2015-01-27 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9745291B2 (en) 2012-12-21 2017-08-29 Epizyme, Inc. PRMT5 inhibitors containing a dihydro- or tetrahydroisoquinoline and uses thereof
US9765068B2 (en) 2012-12-21 2017-09-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9777008B2 (en) 2012-12-21 2017-10-03 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9908887B2 (en) 2012-12-21 2018-03-06 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10118918B2 (en) 2012-12-21 2018-11-06 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10150758B2 (en) 2012-12-21 2018-12-11 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10307413B2 (en) 2012-12-21 2019-06-04 Epizyme, Inc. Tetrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof
US10391089B2 (en) 2012-12-21 2019-08-27 Epizyme, Inc. PRMT5 inhibitors and uses therof
US10980794B2 (en) 2012-12-21 2021-04-20 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10653693B2 (en) 2014-08-04 2020-05-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof

Also Published As

Publication number Publication date
AU2228992A (en) 1993-02-11

Similar Documents

Publication Publication Date Title
US10941113B2 (en) Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10556904B2 (en) Derivatives and methods of treating hepatitis B infections
US9115113B2 (en) Azepane derivatives and methods of treating hepatitis B infections
US9579313B2 (en) Hepatitis B antiviral agents
US10196376B2 (en) Hepatitis B antiviral agents
US9873671B2 (en) Azepane derivatives and methods of treating hepatitis B infections
US9339510B2 (en) Azepane derivatives and methods of treating hepatitis B infections
EP1455777B1 (fr) Inhibiteurs de transporteurs glyt1 et utilisatons de ceux-ci dans le traitement de troubles neurologiques et neuropsychiatriques
JP6903658B2 (ja) インフルエンザウィルス感染に使用するための複素環インドール
CA2969557A1 (fr) Composes de sulfonamide inverse a base de sulfure, alkyle et pyridyle pour le traitement du vhb
US11325916B1 (en) Spiropyrrolidine derived antiviral agents
US20210052585A1 (en) Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same
WO1993001174A1 (fr) Derives de thiazolidine et leur utilisation comme composes antiviraux
KR20010085490A (ko) 이노신 모노포스페이트 디하이드로게나제 저해제로서의옥스아미드
US11639350B2 (en) Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
EP0548798A1 (fr) Agent antiviral
US11365207B2 (en) Sulfur-containing polycyclic-hydroxypyridone carboxamide analog against HIV
WO1994018192A1 (fr) Derives de piperazine utiles comme inhibiteurs de la protease du vih
US20210355129A1 (en) Novel urea 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines active against the hepatitis b virus (hbv)
US20040192707A1 (en) Compounds and methods for the treatment or prevention of Flavivirus infections
WO2023088418A1 (fr) Composés utilisés en tant qu'inhibiteurs de sars-cov-2
WO1992020665A1 (fr) Derives de thiazolidine et utilisation de ces derives a des fins therapeutiques
DE69333270T2 (de) Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
WO2022125613A1 (fr) Phosphonates en tant qu'inhibiteurs d'enpp1 et cdnp
KR100551944B1 (ko) 신규에폭시숙신아미드유도체또는그의염

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH CS DE DK ES FI GB HU JP KP KR LK LU MG MN MW NL NO PL RO RU SD SE US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA