EP1421060A1 - Inhibiteurs de protease antivirale - Google Patents

Inhibiteurs de protease antivirale

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Publication number
EP1421060A1
EP1421060A1 EP02763160A EP02763160A EP1421060A1 EP 1421060 A1 EP1421060 A1 EP 1421060A1 EP 02763160 A EP02763160 A EP 02763160A EP 02763160 A EP02763160 A EP 02763160A EP 1421060 A1 EP1421060 A1 EP 1421060A1
Authority
EP
European Patent Office
Prior art keywords
compound according
phenyl
mmol
alkyl
compound
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.)
Withdrawn
Application number
EP02763160A
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German (de)
English (en)
Inventor
Björn Classon
Bertil Samuelsson
Anna Stanemyr
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.)
Medivir AB
Original Assignee
Medivir AB
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Filing date
Publication date
Application filed by Medivir AB filed Critical Medivir AB
Publication of EP1421060A1 publication Critical patent/EP1421060A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • This invention relates to novel protease inhibitors and in particular to inhibitors of the aspartate protease possessed by certain retroviruses, notably HIV.
  • the invention further relates to the use of such protease inhibitors in the treatment of conditions caused by retroviruses and in the preparation of medicaments for this purpose.
  • the invention also relates to novel synthesis methodology for the facile preparation of protease inhibitors and similar chemical structures.
  • HIV protease is a virally encoded homodimeric protease belonging to the aspartic protease family of enzymes.
  • the human renin and pepsin enzymes also belong to this family. Inhibition of the HIV protease in cell culture prevents viral maturation and replication and thus this enzyme represents an attractive target for antiviral therapy against HTv " in humans.
  • WO 94/13629 describes HIV protease inhibitors based on mannitol esters.
  • Our copending application no. WO98/45330 describes sugar based protease inhibitors based on a mannitol skeleton, but wherein the PI groups are ethers. While the latter compounds are fairly potent and very easy to synthesise, the nature of the HUIV replicative process with its extremely error prone transcription and rapid generation of drug escape mutants means that further more potent compounds with DMPK properties amenable to good patient compliance are required in the HIV armamentarium.
  • a first aspect of the invention provides novel compounds of the formula I:
  • A' and A" are independently the same or different group of the formula II:
  • R' is H, CH 3 , C(CH 3 ) 2 , -OR a , -N(R a ) 2 , -N(R a )OR a or -DP
  • R'" is H or CH 3 ;
  • R a is H, C,-C 3 alkyl;
  • P is an optionally substituted, mono or bicyclic carbo- or heterocycle;
  • R" is H, any of the sidechains found in the natural amino acids, C ⁇ - a alkyl, carboxacetamide, or a group (CH 2 ) n DP;
  • Q is absent, a bond, -CH(OH)- or -CH 2 -; or R" together with Q , M and R' define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring;
  • X is H, OH, OCH 3 ;
  • Y is H, OH, OCH 3 , Z' and Z" are independently an optionally substituted mono-or bicyclic carbo-or heterocycle;
  • () is a methylene group; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof.
  • Compounds of the formula I are active inhibitors of aspartyl proteases, such as those from HIV. Further aspects of the invention thus provide: - a pharmaceutical formulation comprising a compound of the formula I in admixture with a pharmaceutical acceptable carrier or diluent;
  • the compounds have a relatively low molecular weight and should therefore provide good oral absorption properties in mammals.
  • terminal amines A' and A" are identical.
  • the target enzyme is a symmetric dimer, thus implying a tight interaction with symmetric compounds, it can in some circumstances be advantageous for resistance or pharmacokinetic reasons etc to have asymmetric terminal amines.
  • the differential terminal amination can be achieved with a solid phase synthesis where the unprotected or partially protected diepoxydicarboxy acid is secured to a solid phase substrate, such as polymer beads of which many are known in solid phase chemistry, for instance Merrifield resin, in conjunction with an appropriate linker structure. Immobilization of the diepoxydicarboxylic acid in this fashion will only allow amination of one carboxy group. Cleavage from the resin/linker releases the other carboxy terminal which is subsequently amidated with the second terminal amine using conventional peptide chemistry.
  • a solid phase substrate such as polymer beads of which many are known in solid phase chemistry, for instance Merrifield resin
  • Preparation of compounds of Formula I in which X is hydrogen can be carried out by deoxygenation analogously to Examples 2 and 26 of WO 9845330.
  • X and Y are not both H.
  • a preferred stereochemistry is the 2R, 3R, 4R, 5R form, the synthesis of which is shown in the examples.
  • a further preferred stereochemistry is
  • Carbocyclic groups for R' as -DP and/or Z'/Z" and/or the optional substituents thereto may be saturated, unsaturated or aromatic and include monocyclic rings such as phenyl, cyclohexenyl, cyclopentenyl, cyclohexanyl, cyclopentanyl, or bicyclic rings such as indanyl, napthyl and the like.
  • Heterocyclic groups for R' as -DP and/or Z'/Z" and/or the optional substituents thereto may be saturated, unsaturated or aromatic and have 1 to 4 hetero atoms including monocyclic rings such as furyl, thienyl, pyranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like or bicyclic rings especially
  • Preferred embodiments of Formula II for the A7A" groups of the compounds of the invention include those of the formula Ha or lie:
  • n is 1 or 2 and R' is alkyloxy, preferably methyloxy, or those where n is 0 and R' is methyl.
  • Q is a bond, methylene or-C(OH)- and R' is -OR a , -N(R a ) 2 , -NR a OR a , where R a is H or C 1 -C 3 alkyl, or a carbo- or heterocyclic group including N-piperidine, N-morpholine, N- piperazine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl etc .
  • R d is hydrogen or methyl (that is a valyl or isoleucyl side chain) and R e is
  • R" is hydrogen, methyl, ethyl, isopropyl, cycloalkyl such as cyclopropyl, cyclobutyl or cyclohexyl, cycloalkenyl, benzyl, carboxacetamide or 4- imidazolylmethy, any of which may be substituted as defined above.
  • Preferred R" groups include the side chains found in the natural amino acids, especially those of leucine, asparagine, histidine or proline.
  • the most preferred R" groups for formula Ila, lib, lie and lid are the tertiary leucyl, isoleucyl and especially the valyl side chain.
  • R' will vary depending on the nature of Q and/or M, if present, and may for instance be selected from hydrogen, methyl, ethyl, isopropyl, R e as defined above, valinol, a heterocycle such as pyridyl, thiazole, oxazole, imidazole, N-piperidine, N-morpholine, N-piperazine, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, pyrazinyl, any of which R' groups may be substituted as defined for Z'/Z" below.
  • A'/A" groups include those of formula II where R", Q, M and R' together define an optionally substituted 5 or 6 membered carbo- or heterocylic ring.
  • a preferred group within this definition include groups within formula III:
  • R' is as defined above
  • R 2 s OH, or together with R' is O, or if R' is NR 4 R ⁇ then R' may be H; R 3 s H, halo, C 1 -C 3 alkyl, OR 5 , NR 4 R 4 ; R 4 s H, C ⁇ -C 3 alkyl; R 5 s H or a pharmaceutically acceptable ester; R 6 s OH, NH 2 , carbamoyl or carboxy;
  • R 7 s hydrogen, C 1 -C 4 straight or branched alkyl or together with the adjacent carbon atoms forms a fused phenyl or heteroaromatic ring;
  • Preferred groups of formula III include aminoindanol and 1 -amino-azaindan-2-ol, that is moieties of the formulae:
  • Optional substitutents for the carbo- or heterocyclic moiety of Z'/Z" or A'/A" include one to three substituents such as halo, amino, mercapto, oxo, nitro, NHC ⁇ -C 6 alkyl, N(C ⁇ -C 6 alkyl) 2 , C ⁇ -C 6 alkyl, C C 6 alkenyl, C ⁇ -C 6 alkynyl, C C 6 alkanoyl, C ⁇ -C 6 alkoxy, thioC ⁇ -C 6 alkyl, thioC C 6 alkoxy, hydroxy, hydroxyC ⁇ -C 6 alkyl, haloC C 6 alkyl, aminoC C 6 alkyl, C C 6 alkyl, cyano, carboxyl, carbalkoxy, carboxamide, carbamoyl, sulfonylamide, benzyloxy, morpholyl-C r C 6 alkyloxy, a monocyclic carbo- or heterocycle,
  • the preferred definitions for -() m Z' and - ⁇ ) m Z" include benzyl and especially phenethyl each unsubstituted or substituted with 1 , 2 or 3 substituents, especially 1 selected from fluoro, chloro, hydroxy, amino, -NH(C 1-6 alkyl), -N(C ⁇ -6 alkyl) 2 , -NPh(C,. 6 alkyl), -NHPh, methoxy, cyano, hydroxymethyl, aminomethyl, alkylsulfonyl, carbamoyl, mo ⁇ holinethoxy, benzyloxy, benzylamide etc.
  • substituents especially 1 selected from fluoro, chloro, hydroxy, amino, -NH(C 1-6 alkyl), -N(C ⁇ -6 alkyl) 2 , -NPh(C,. 6 alkyl), -NHPh, methoxy, cyano, hydroxymethyl, aminomethyl, alkylsulf
  • substituent to Z' and/or Z" may comprise a ring structure (which substituent ring structure is itself substituted as defined herein) such as phenyl or a 5 or 6 membered heterocycle containing one or two hetero atoms such as thiophene, pyridine etc.
  • a ring structure which substituent ring structure is itself substituted as defined herein
  • the preparation of useful heterocyclic substituents for Z' and Z" phenyl are described in Tetrahedron Letters 1997 6359-6359-6367 and J Org Chem 62 (1997) 1264 and 6066, including N-morpholine, N-piperidine, N-piperazine, N'-methyl- N-piperazine, N-pyrrolidone, N-pyrrolidine and the like.
  • Such substituents may be in the meta but especially the ortho or para positions of Z'/Z", with small groups such as fluoro being favoured for the ortho and meta and with extensive freedom for larger groups in the para such as (optionally substituted) cyclic substituents, including the N-bonded rings in the immediately preceding paragraph.
  • the whole Z' and Z" group or their respective carbo-or heterocyclic moiety may be different but for ease of synthesis it is convenient if they are the same.
  • Appropriate pharmaceutically acceptable salts both for A'/A" as a free acid or for other charged groups along the compound of formula I include salts of organic carboxylic acids such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic, isethionic, oxalic, lactobionic, and succinic acids, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p- toluenesulfonic acid; and inorganic acids such as hydrochloric, hydroiodic, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic, isethionic, oxalic, lactobionic, and succinic acids
  • Prodrugs of the invention are derivatives that release a compound of formula I in vivo, generally by hydrolysis or other metabolic interaction in the intestine, liver or plasma.
  • Typical prodrugs are esters formed on free hydroxy groups in the compounds.
  • Appropriate pharmaceutically acceptable esters include C ⁇ -C 22 fatty acid esters, where the fatty acid is unsaturated, monounsaturated or multiply unsaturated.
  • Saturated fatty acid esters include short chains such as acetyl or butyryl or long chain such as stearoyl.
  • Unsaturated fatty acid esters are preferably in the ⁇ -9 series, such as palmitoleic or linolenic esters.
  • Other esters include Ci-C ⁇ alkylaryl esters such as benzyl or methylpyridyl or esters of phosphoric acid, such as monophosphate.
  • Alternative esters include the corresponding fatty acid or alkylaryl carbonate, carbamate or sulphonic esters.
  • Particularly favoured prodrugs include those described in WO99/41275, especially when A' and A" comprise an hydroxy function such as aminoindanol.
  • the compounds of formula I are preferably administered in an amount to achieve a plasma level of around 10 to 1000 nM and more preferably 100 to 500 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation of the order 0.001 to 100 mg/kg/day, preferably 10 to 50 mg/kg/day.
  • molar ratio for such co-administered antivirals will generally be chosen to reflect the respective EC 50 performances of the antiviral. Molar ratios of 25:1 to 1 :25, relative to the compound of formula I will often be convenient.
  • the active agent While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation.
  • a pharmaceutical formulation will comprise the above defined active agent together with one or more acceptable carriers and optionally other therapeutic 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.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the above defined active agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
  • suitable carrier includes vehicles such as common excipients e.g.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate and other metallic stearates, stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • Formulations suitable for topical administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, and pastes comprising the active agent and a pharmaceutically active carrier.
  • An exemplary topical delivery system is a transdermal patch containing the active agent.
  • Formulations for rectal or vaginal administration may be presented as a suppository or pessary with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Other vaginal preparations can be presented as tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active agent, such carriers as are known in the art to be appropriate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation from a container of the powder held up close to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active agent.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
  • ⁇ aH (1.61 g, 67.1 mmol, 1.1 equiv.) was suspended in DMF (150 mL) under an argon atmosphere and the temperature was lowered to 0 °C.
  • a dropping funnel was charged with the chiral auxiliary 1 (10.7 g, 61.2 mmol) in DMF (90 mL), a second dropping funnel was charged with 4-phenylbutanoyl chloride (13.4 g, 73.4 mmol, 1.2 equiv.) in DMF (90 mL) and the two solutions were then added simultaneously to the stirred NaH suspension during 30 min.
  • Trioxane (2.08 g, 23.1 mmol, 0.74 equiv.) and TiCl 4 (4.5 mL, 40.9 mmol, 1.3 equiv.) were added, and stirring was continued until TLC (R / 0.15, toluene- EtOAc 10:1) showed complete reaction (3 h). During this time the colour of the reaction changed from dark red to light brown.
  • Neutralisation (pH 7) of the cold reaction was performed by adding sat. aqueous NaHC0 3 (500 L). The layers were separated and the aqueous layer was extracted with CH 2 C1 2 (4x). The combined organic layers were dried (Na 2 S0 4 ) and concentrated.
  • the benzylated compound 4 (3.85 g, 8.72 mmol) was dissolved in THF (90 mL) under an argon atmosphere, the temperature was lowered to -60 °C and LAH (3.38 g, 89.0 mmol, 10 equiv.) was added. Stirring was continued at -60 °C for 30 min and at 0 °C for 1 h (R / 0.2, toluene-EtOAc 9:1). The reaction mixture was acidified by the addition of cold 0.6 M HC1. The suspension was extracted with Et 2 0 (5x) and the combined organic layers were dried (MgS0 4 ) and concentrated.
  • Moshers ester of alcohol 5 was prepared according to the method described by Wipf and Fritch, using 26 mg (0.096 mmol) of 5 in 1.4 ml of CH 2 C1 2 together with 580 GL of pyridine and 210 DL of (S)-(+)-D -methoxy- D-(trifluoromethyl)phenylacetic acid chloride with stirring during 40 min.
  • Moshers ester of racemic alcohol 5 was prepared as described above, using 20 mg (0.074 mmol) of racemic 5, which gave the racemic ester (28 mg, 0.058 mmol, 78%) as an oil: 13 C NMR (75 MHz, CDC1 3 ) Q 29.8, 29.9, 33.0, 37.8 (2 C), 55.4, 66.2, 66.4, 69.6, 69.7, 73.2, 121.4, 125.2, 125.8, 127.2, 127.4 (2 C), 127.5, 128.2, 128.3, 129.5, 138.1 and 141.5.
  • Aldehyde 6 was reduced with BMS according to the method described by Brown et al. , using 64 mg (0.238 mmol) of 6 in 2.0 ml of diethyl ether together with 60 DL of BMS with stirring at 0 °C during 30 min, followed by stirring at room temperature during 2.5 h. Purification by column chromatography (toluene-EtOAc 3: 1) gave alcohol 5 (50 mg, 0.185 mmol, 78%>) as an oil. Alcohol 5 (20 mg, 0.074 mmol) was converted to Moshers ester (28 mg, 0.058 mmol, 78%) according to the method described above.
  • Zinc dust pre-washed with 1M HC1, EtOH, acetone and CH 2 C1 2 ) (2.72 g, 41.6 mg-atom, 2.0 equiv.) was added to a solution of VC1 3 (THF) 3 in CH 2 C1 2 (50 mL, 0.5 M, 25 mmol, 1.2 equiv.), under an argon atmosphere, changing the colour of the solution from deep-red to violet. The mixture was stirred at room temperature during 80 min, while the colour slowly changed from violet to black-green.
  • Step III Hydrogenolysis.
  • Compounds 8 a-c (1.0 equiv.) was dissolved in EtOAc (23 mL/mmol), and NaHCO 3 (3.0 equiv.), a minor amount of H O and Pd/C (0.8 g) was added.
  • the suspension was stirred at room temperature under a hydrogen atmosphere. After 19 h, 39 h and 47 h, the suspension was filtered through a pad of Celite and Na 2 SO 4 , fresh reagents were added and stirring under hydrogen was continued.
  • the title compound was prepared according to method III, using 153 mg (0.247 mmol) of the disuccinimidyl ester 10 b, and isolated as a white solid in 7% yield (10 mg, 0.017 mmol) together with recovered 13 a (26 mg, 0.040 mmol).
  • the title compound was prepared according to method III, using 52 mg (0.084 mmol) of the disuccinimidyl ester 10 b, and isolated as a white solid in 22% yield (1 1 mg, 0.018 mmol) together with recovered 13 b (16 mg, 0.025 mmol).
  • MT4 cells grown in RPMI 1640 cell culture medium including 10 % fetal calf serum are infected with 10 TCID HIV-1 per 2 x 10 5 cells and cultured for 6 days.
  • XTT is added and the amount of XTT formazan produced in the following 6 hours represents the number of surviving cells.
  • Results are expressed as the ED 5 o, that is the concentration in ⁇ g/ml of the compound of the invention which suppresses viral replication by 50%. Additionally, activity measurements are run in the corresponding system further comprising 40% human serum to mimic protein binding effects in vivo.
  • Example 10 of WO98/45330 The compounds of the invention have a particularly good performance in the presence of human serum relative to the closest compounds of the prior art .

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Abstract

L'invention concerne des composés de la formule (I) où X et Y représentent hydroxy ou H. A' et A'' sont des fonctions amine terminale telles que valinamide ou indanolamine. Z', Z'' et les ( )n groupes adjacents représentent indépendamment alkylaryle. Ces composés sont utiles comme inhibiteurs d'aspartyle sida-protéase ayant une activité particulièrement bonne en présence de sérum humain.
EP02763160A 2001-08-29 2002-08-29 Inhibiteurs de protease antivirale Withdrawn EP1421060A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE0102892 2001-08-29
SE0102892A SE0102892D0 (sv) 2001-08-29 2001-08-29 Antivirals I
PCT/SE2002/001549 WO2003018537A1 (fr) 2001-08-29 2002-08-29 Inhibiteurs de protease antivirale

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EP1421060A1 true EP1421060A1 (fr) 2004-05-26

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EP02763160A Withdrawn EP1421060A1 (fr) 2001-08-29 2002-08-29 Inhibiteurs de protease antivirale

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EP (1) EP1421060A1 (fr)
JP (1) JP2005501118A (fr)
CA (1) CA2458040A1 (fr)
IL (1) IL160626A0 (fr)
SE (1) SE0102892D0 (fr)
WO (1) WO2003018537A1 (fr)

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WO2014169456A1 (fr) * 2013-04-18 2014-10-23 西安力邦医药科技有限责任公司 Utilisation de 7-a-[9-(4,4,5,5,5-pentafluoro-pentyl-sulfinyl)nonyl]-estra-1,3,5(10)-triène-3,17b-diol et de ses dérivés

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SE9701245D0 (sv) * 1997-04-04 1997-04-04 Bjoern Classon Antivirals

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* Cited by examiner, † Cited by third party
Title
See references of WO03018537A1 *

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WO2003018537A1 (fr) 2003-03-06
IL160626A0 (en) 2004-07-25
JP2005501118A (ja) 2005-01-13
SE0102892D0 (sv) 2001-08-29
CA2458040A1 (fr) 2003-03-06

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