Nothing Special   »   [go: up one dir, main page]

WO1993002674A1 - Inhibiteurs de la protease du vih - Google Patents

Inhibiteurs de la protease du vih Download PDF

Info

Publication number
WO1993002674A1
WO1993002674A1 PCT/US1992/006373 US9206373W WO9302674A1 WO 1993002674 A1 WO1993002674 A1 WO 1993002674A1 US 9206373 W US9206373 W US 9206373W WO 9302674 A1 WO9302674 A1 WO 9302674A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
butoxycarbonylamino
phenylmethyl
phenyl
compound according
Prior art date
Application number
PCT/US1992/006373
Other languages
English (en)
Inventor
Geoffrey Bainbridge Dreyer
Renee Desjarlais
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO1993002674A1 publication Critical patent/WO1993002674A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention relates to non-peptide inhibitors of proteases encoded in retroviruses, in particular, to inhibitors of the virally encoded protease of the Human Immunodeficiency Virus.
  • Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than
  • RNA-tumor viruses also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals. They are believed to be the causative agents in pathological states associated with infection by Rous sarcoma virus (RSV), murine leukemia virus (MLV), mouse mammary tumor virus (MMTV), feline leukemia virus (FeLV), bovine leukemia virus (BLV), Mason-Pfizer monkey virus (MPMV), simian sarcoma virus (SSV), simian acquired immunodeficiency syndrome (SAIDS), human T- lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2), which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related complexes, and many others.
  • RSV Rous sarcoma virus
  • MMV murine leukemia virus
  • MMTV mouse mammary tumor virus
  • FeLV fel
  • transcriptase such as 3'-azido-3'-deoxythymidine and 2',3'- dideoxycytidine. These treatments have not proven effective to arrest or reverse the disease, they may have adverse side effects, and they may lose their efficacy over time.
  • Virally-encoded proteases function in many of these viruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins.
  • the proteolytic activity provided by the virally-encoded protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. It has been
  • retroviruses which lack a protease or contain a mutated form of it, lack infectivity. See Katoh et al.. Virology, 145, 280-92(1985), Crawford, et al., J .
  • protease which contain a symmetrical isostere are reported in EP-A 402 646. There remains a need for protease inhibiting compounds which have a favorable balance of potency and pharmacokinetic properties.
  • This invention comprises compounds, hereinafter, of the formula (I), which inhibit the retroviral protease of HIV-1, and are useful for treating infection by the human
  • This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a
  • This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I).
  • R 1 , R 1' , R 4 , R 5 are independently H, C 1-6 alkyl, C 2-6 alkenyl,
  • T is Ar, Het or C 3-7 cycloalkyl
  • R 3 is H or OH
  • Q is OH or NH 2 ;
  • W is R 6 , R 6 CO, R 6 OCO, R 6 OCH (R 7 ) CO, R 6 NHCH (R 7 ) CO,
  • R 6 and R 7 are independently H, C 1-6 alkyl, C 3-7 cycloalkyl,
  • Y is H; OH, NR'R 4 , Ar, Het or CO-Z;
  • Z is OH, NR'R 4 , OR 4 or an amino acid with a blocked or unblocked carboxy terminus
  • R' is H, C 1-6 alkyl, Ar-C 1-6 alkyl;
  • n 1 to 4.
  • R 1 and R 1 ' are benzyl.
  • R 3 is hydrogen
  • R 2 is CH(isopropyl) -Y, CH 2 -phenyl, CHR 4 (2- imidazolyl) or CH(i-propyl) CO-Z.
  • Representative compounds of this invention are:
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • the compounds of this invention have favorable
  • pharmacokinetic properties are useful, in particular, for the treatment of infections by the human immunodeficiency virus.
  • Ar or aryl, as applied herein, means phenyl or
  • naphthyl or phenyl or naphthyl substituted by one to three C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkthio, trifluoroalkyl, guanidino, amidino, HetC ⁇ -4alkoxy, HetC 1-4 alkyl, OH, Cl, Br or I.
  • Het, or heteroaryl indicates a five or six membered aromatic ring, or a nine or ten-membered aromatic ring, containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
  • heterocycles are morpholine, tetrazole, imidazole,
  • Het ring may optionally be substituted by a C 1-4 alkyl or C 1-4 alkenyl or C 1-4 alkoxy group.
  • Boc refers to the t-butyloxycarbonyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • Bzl refers to the benzyl radical
  • Ac refers to acetyl
  • Ph refers to phenyl
  • EDTA is ethylenediamine tetraacetic acid
  • DIEA diisopropyl
  • C 1-6 alkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl and hexyl, isohexyl, 3- methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, and 1-ethylbutyl.
  • C 2-6 alkenyl as applied herein means
  • Ar-C 1-6 alkyl and Ar- C 2-6 alkenyl mean C 1-6 alkyl or C 2-6 alkenyl wherein a carbon- hydrogen bond is replaced by a carbon-Ar bond.
  • Het-C 1-6 alkyl and Het-C 2-6 alkenyl mean C 1-6 alkyl or C 2-6 alkenyl wherein a carbon-hydrogen bond is replaced by a carbon-Het bond.
  • AA as used herein indicates one to three amino acids, which may be:
  • Glutamine or Glutamic Acid Glx When Y is a CO-Z and Z is an amino acid, the amino acid is joined by an amide bond via its amino terminus to the carbonyl group, and the carboxy terminus of the amino acid is blocked or unblocked. An unblocked carboxy terminus is a free carboxyl group.
  • Typical blocking groups are esters and amides, such as NR T R 4 or OR 4 ., wherein R 6 and R 7 are as defined in formula (I).
  • W is an amino acid
  • the amino acid is joined via its carboxy terminus to the amino group, and the amino terminus of the amino acid may be blocked or unblocked.
  • Valine and alanine are useful amino acids
  • Cbz-Val and 2- quinolinylcarbonyl-Val are illustrative blocked amino acids.
  • An unblocked amino terminus is an unsubstituted amino group.
  • Typical blocking groups for the amino terminus are R 6 , R 6 CO, R 6 OCO, R 6 OCH(R 7 )CO, R 6 NHCH(R 7 ) CO, R 6 SCH(R 7 )CO, R 6 SO 2 or R 6 SO, wherein R 6 and R 7 are as defined in formula (I).
  • Illustrative substituents are acetyl, Boc, Cbz, pyridinylmethyloxycarbonyl and 3-quinolinylmethyloxycarbonyl.
  • the compounds of this invention are prepared by:
  • Compounds of the structure 1 are prepared by reacting an appropriately protected hydroxyethylene isostere, such as methyl 5-t-butoxycarbonylamino-4-t-butyldimethylsilyloxy-6- phenyl-2-phenylmethyl-hexanoate or 5-[(1'-N-t- butoxycarbonylamino-2'-phenyl)-ethyl]-3-phenylmethyl- ⁇ - butyrolactone, with dimethyl methylphosphonate in the
  • a strong base such as n-butyllithium or lithium diisopropylamide
  • an inert solvent such as
  • Compounds of the structure 2 are prepared by reacting the carboxylic acid of an appropriately protected hydroxyethylene isostere, such as methyl 5-t- butoxycarbonylamino-4-t-butyldimethylsilyloxy-6-phenyl-2- phenylmethyl-hexanoic acid, with O,N-dimethylhydroxylamine in the presence of a suitable coupling reagent, such as a carbodiimide or BOP reagent (benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafluorophosphate.
  • an appropriately protected hydroxyethylene isostere such as methyl 5-t- butoxycarbonylamino-4-t-butyldimethylsilyloxy-6-phenyl-2- phenylmethyl-hexanoic acid
  • a suitable coupling reagent such as a carbodiimide or BOP reagent (benzotriazol-1- yloxytris (dimethyla
  • an appropriate acyl intermediate such as 2,5-disubstituted-4-hydroxy-5-amino- pentanoic(N-methyl,N-methoxy) amide, wherein the hydroxyl and amino groups are suitably protected as is common in the art, is treated with an appropriate nucleophile, such as a
  • organocopper reagent or other suitable carbon nucleophile in an inert solvent, such as THF, to yield a ketone. If lithium acetylide is used as the nucleophile an ⁇ , ⁇ -acetylenic ketone is prepared. Subsequent reduction of the triple bond to a double bond, such as with Lindlar's catalyst or 5% palladium on BaSO 4 in the presence of quinoline, yields the
  • a fluoride reagent such as
  • tetrabutylammonium fluoride is suitable.
  • a ⁇ - keto-phosphonate is reacted with an appropriate aldehyde or ketone to yield an ⁇ , ⁇ -unsaturated ketone.
  • compound JL may be reacted in an appropriate solvent, such as THF, with an aldehyde or ketone, such as benzaldehyde, isobutyraldehyde or l-benzyloxymethyl-2-formyl-imidazole or glyoxylamide to provide the corresponding ⁇ -substituted ketones.
  • the unsaturated ketone may be reduced, as described for Scheme 1, or further reacted, as in Scheme 3 or by other methods common in the art, to introduce functionality into the molecule.
  • nitrile which may be further converted to an amide or acid by methods common to the art.
  • Carboxylic acids may, of course be converted to esters, amides and alcohols.
  • Other typical reactions to introduce functionality into the ⁇ , ⁇ -unsaturated ketone are epoxidation of the double bond and conjugate addition of nucleophiles to the double bond, as illustrated in Scheme 4.
  • Reaction of an aldehyde for instance with sodium borohydride in methanol, yields an alcohol.
  • Reaction of the aldehyde with glyoxal and ammonia yields an imidazole.
  • ⁇ , ⁇ unsaturated ketone 3 treatment of ⁇ , ⁇ unsaturated ketone 3 with alkaline hydrogen peroxide in an alcoholic solvent, or m-chloroperbenzoic acid or trifluoroperoxyacetic acid in a halocarbon solvent, such as methylene chloride, yields an ⁇ , ⁇ -epoxy ketone.
  • the epoxide may be further reacted with diethylaluminum cyanide to provide an ⁇ - hydroxy, ⁇ -cyano ketone.
  • the cyano group may be hydrolyzed by methods common to the art to give an acid or an amide, and further converted to derivatives thereof, such as an ester.
  • the epoxide may be reacted with an organo cuprate reagent, such as lithium divinyl cuprate or lithium di-(1-methoxy-vinyl) cuprate, to yield the organo cuprate reagent, such as lithium divinyl cuprate or lithium di-(1-methoxy-vinyl) cuprate, to yield the organo cuprate reagent, such as lithium divinyl cuprate or lithium di-(1-methoxy-vinyl) cuprate, to yield the organo cuprate reagent, such as lithium divinyl cuprate or lithium di-(1-methoxy-vinyl) cuprate, to yield the organo cuprate reagent, such as lithium divinyl cuprate or lithium di-(1-methoxy-vinyl) cuprate, to yield the organo cuprate reagent, such as lithium divinyl cuprate or lithium di-(1-methoxy-vinyl) cuprate, to yield the organo cuprate reagent, such as lithium divinyl cuprate or lithium di
  • a group other than a protecting group is desired for the substituent W, then the protecting group is removed and the amino group is reacted with an appropriate alkylating or acylating reagent.
  • Alkyl halides, acyl halide, sulfonyl halides, anhydrides, activated esters, and the like, of the appropriate group W are useful for this purpose.
  • Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
  • an acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
  • the acetate salt form is especially useful. If the final compound contains an acidic group, cationic salts may be prepared.
  • the parent compound such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
  • an alkaline reagent such as a hydroxide, carbonate or alkoxide, containing the appropriate cation.
  • Cations such as Na + , K + , Ca ++ and NH 4 + are examples of cations present in pharmaceutically
  • Certain of the compounds form inner salts or zwitterions which may also be acceptable.
  • the compounds of formula (I) are used to induce antiviral activity in patients which are infected with susceptible viruses and require such treatment.
  • the method of treatment comprises the administration orally,
  • Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection.
  • the compounds of this invention are particularly useful for the treatment of HIV-1. No unacceptable toxicological effects are expected when compounds of the invention are administered in
  • compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral
  • compositions may be added to enhance or stabilize the
  • Liquid carriers include syrup, peanut oil, olive oil,
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
  • Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention.
  • anti-viral agents examples include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen.
  • Nucleoside analogues which include 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyadenine (ddA) and 3'-azido-2',3'-dideoxythymide (AZT), are especially useful.
  • AZT is one preferred agent.
  • pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting compound of this invention and a pharmaceutically acceptable carrier.
  • protease inhibiting properties of the compounds of this invention are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 0.5 ⁇ M to about 2 mM.
  • the enzyme used to assay the compound of this invention was produced in this manner and purified from the cell pellet as follows.
  • the E. coli cell pellet was resuspended in a buffer consisting of 50 mM Tris-HCl, pH 7.5; 1.0 mM each DTT, EDTA and PMSF
  • the column was equilibrated in the same buffer at a flow rate of 4 mL/min.
  • the effluent of the column was monitored at 280 nm and 1 min. fractions collected.
  • the rHIVPRT recombinant HIV protease
  • the protease was 85-95% pure.
  • By immunoblot analysis >90% of the immunoreactive material was precipitated at the ammonium sulfate step.
  • activity assay the highest peak of activity was found in the fractions collected at 45 and 46 minutes. Analysis of the TSK column fractions by RP- HPLC and SDS-PAGE indicated that the majority of the 11,000 Mr protein is also found in fractions 45 and 46.
  • the activity itself cannot be used to obtain reliable recovery data as it is influenced by high salt, i.e., with increasing salt, increasing levels of activity were obtained. Thus, with each step in the purification, more total activity was recovered than was started with.
  • the overall yield of rHIVPRT was 1 mg from a 50 g E. coli cell pellet.
  • MENDT buffer 50 mM Mes (pH 6.0; 2- (N-morpholino) ethanesulfonic acid), 1 mM
  • reaction mixtures 37°C were quenched after 10-20 minutes with an equal volume of cold 0.6 N trichloroacetic acid, and, following centrifugation to remove precipitated material, peptidolysis products were analyzed by reverse phase HPLC (Beckman Ultrasphere ODS, 4.5 mm x 25 mm; mobile phase: 5-20% acetonitrile/H2 ⁇ - 0.1% TFA (15 min), 20% acetonitrile/H 2 O -
  • step 1(a) The benzyl lactone of step 1(a) (1.01 g, 0.0026 mol) in dioxane (2.8 mL) and water (1.4 mL) was treated with sodium hydroxide (1 M, 4.25 mL, 0.00425 mol). The solution was stirred for 15 min after which time citric acid (5% aqueous, 80 mL) was added and the mixture extracted with diethyl ether (3 x 75 mL). The combined extracts were dried (sodium sulphate), filtered, and the solvents removed in vacuo.
  • step 1(d) The phosphonate of step 1(d) (0.128 g, 0.0002 mol) was dissolved in THF (3 mL). Potassium carbonate (0.300 g, 0.002 mol) was added followed by isobutyraldehyde (183 ⁇ L, 0.002 mol) and the mixture stirred for 48 h. After this time water (5 mL) was added and the mixture was extracted with diethyl ether (3 x 50 mL). The combined extracts were re-extracted with 20% sodium bisulphite solution (20 mL), dried (sodium sulphate), filtered, and concentrated in vacuo .
  • Cis 1 HNMR (CDCI 3 , 250 MHz) ⁇ -0.06 (s, 3 H), 0.03 (s, 3 H),
  • step 3(a) The phosphonate of step 3(a) (25.5 mg, 0.05 mmol) was dissolved in THF (1 mL) and water (0.5 mL). Potassium carbonate (50 mg, 0.4 mmol) was added followed by
  • Example 5 (a) The compound of Example 5 (a) (30 ⁇ mol) is dissolved in trifluoroacetic acid (1 mL) and stirred at room temperature for 10 min. The trifluoroacetic acid is evaporated and the residue is dissolved in THF (0.5 mL) and triethylamine is added (150 ⁇ mol) followed by benzyl chloroformate (36 ⁇ mol).
  • Example 5(b) The compound of Example 5(b) (25 ⁇ mol) is dissolved in methanol (0.5 mL) at 0°C and treated with saturated
  • Example 5 (c) The compound of Example 5 (c) (30 ⁇ mol) was treated with tetrabutyl ammonium fluoride in THF (1M in THF, .18 mmol) for 4 h. The reaction mixture is diluted with methylene
  • Example 1(d) The phosphonate of Example 1(d) (0.5 mmol) is dissolved in THF (10 mL) and DBU (1 mmol) is added. 1-Benzyloxymethyl- 2-formyl-imidazole (1 mmol) is added and the reaction is stirred for two days at room temperature. The reaction mixture is diluted with methylene chloride and the organic phase is washed with 5% HCl, water and brine. The organic extract is concentrated to a crude residue, which is
  • Example 6(a) The compound of Example 6(a) (0.1 mmol) is dissolved in methanol (5 mL) and hydrogenated at 60 psi over 5% palladium on carbon (5 mg) overnight. The catalyst is removed by filtration. The reaction mixture is treated with Triton-B according to the procedure of Andersen et al., Tet. Lett., 34, 3165 (1971), to complete removal of the benzyloxymethyl protecting group and yield the title compound.
  • Example 6(b) is desilylated according to the procedure of Example 4(b) to yield the title compound.
  • the reaction is quenched by the addition of 5% aqueous ammonium chloride, diluted with ethyl acetate and washed with aqueous ammonium chloride/ammonium hydroxide solution (9:1 5% aq. NH 4 Cl:conc. NH 4 OH).
  • aqueous ammonium chloride/ammonium hydroxide solution (9:1 5% aq. NH 4 Cl:conc. NH 4 OH).
  • the organic phase is washed with water and brine, and dried over sodium sulphate. Filtration and evaporation of the ethyl acetate solution, and chromatography (silica) yields the title compound.
  • Example 7(a) (0.15 mmol) is hydrogenated and the benzyloxymethyl protecting group is removed according to the procedure of Example 6(b) to yield the title product.
  • c) (9S,8S,6R,2RS)-10-phenyl-9-t-butoxycarbonylamino-8- hydroxy-6-phenylmethyl-5-oxo-3-(2-imidazolyl)-2-methyl-decane
  • Example 7(b) The compound of Example 7(b) (0.1 mmol) is desilylated according to the procedure of Example 4 (b) to yield the title compound.
  • a preparation which contains 25 mg of a compound of this invention is prepared as follows:
  • 25 mg of the compound is dissolved in 15 mL of distilled water.
  • the solution is fi ⁇ :ered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized.
  • the powder is reconstituted by addition of 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection.
  • D5W dextrose in water
  • the dosage is thereby determined by the injection volume.
  • This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion.
  • a capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and 30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.

Landscapes

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

Abstract

L'invention se rapporte aux composés de la formule (I), dans laquelle R?1, R1', R3, R4, R5¿ représentent séparément H, C¿1-6?alkyle, C2-6alkényle, C3-7cycloalkyle, Ar, Het, T-C1-6alkyle, T-C2-6alkényle; T représente Ar, H et ou C3-7 cycloalkyle; R?2¿ représente Y, (CHR4)n-Y, =CR5(CHR4)n-Y; R3 représente H, OH; Q représente OH ou NH¿2?; W représente R?6, R6CO, R6OCO, R6OCH(R7)CO, R6NHCH(R7)CO, R6SCH(R7)CO, R6SO¿2, R6SO ou un acide aminé à extrémité terminale amino bloquée ou débloquée; R6 et R7 représentent séparément H, C¿1-6?alkyle, C3-7cycloalkyle, Ar, Het, T-C1-6alkyle, T-(CH2)nCH(T)(CH2)n; X représente (H,OH) ou =O; Y représente H; OH, NR'R?4¿, Ar, H et ou CO-Z; Z représente OH, NR'R4, OR4 ou un acide aminé à extrémité terminale carboxy bloquée ou débloquée; R' représente H, C¿1-6?alkyle, Ar-C1-6alkyle; n représente 1 à 4; et des sels de celui-ci pharmaceutiquement acceptables sont des inhibiteurs de la protéase VIH-1 et sont utilisés dans le traitement du SIDA.
PCT/US1992/006373 1991-08-02 1992-07-31 Inhibiteurs de la protease du vih WO1993002674A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73956091A 1991-08-02 1991-08-02
US739,560 1991-08-02

Publications (1)

Publication Number Publication Date
WO1993002674A1 true WO1993002674A1 (fr) 1993-02-18

Family

ID=24972861

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/006373 WO1993002674A1 (fr) 1991-08-02 1992-07-31 Inhibiteurs de la protease du vih

Country Status (1)

Country Link
WO (1) WO1993002674A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115652B2 (en) 2002-06-17 2006-10-03 Sunesis Pharmaceuticals, Inc. Aspartyl protease inhibitors
US7132568B2 (en) 2002-06-17 2006-11-07 Sunesis Pharmaceuticals, Inc. Aspartyl protease inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116835A (en) * 1988-12-09 1992-05-26 Hoechst Aktiengesellschaft Enzyme-inhibiting urea derivatives of dipeptides, a process for the preparation thereof, agents containing these, and the use thereof
US5126326A (en) * 1989-06-06 1992-06-30 Bio-Mega, Inc. Enzyme inhibiting peptide derivatives
US5151438A (en) * 1989-05-23 1992-09-29 Abbott Laboratories Retroviral protease inhibiting compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116835A (en) * 1988-12-09 1992-05-26 Hoechst Aktiengesellschaft Enzyme-inhibiting urea derivatives of dipeptides, a process for the preparation thereof, agents containing these, and the use thereof
US5151438A (en) * 1989-05-23 1992-09-29 Abbott Laboratories Retroviral protease inhibiting compounds
US5126326A (en) * 1989-06-06 1992-06-30 Bio-Mega, Inc. Enzyme inhibiting peptide derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115652B2 (en) 2002-06-17 2006-10-03 Sunesis Pharmaceuticals, Inc. Aspartyl protease inhibitors
US7132568B2 (en) 2002-06-17 2006-11-07 Sunesis Pharmaceuticals, Inc. Aspartyl protease inhibitors

Similar Documents

Publication Publication Date Title
US20220259145A1 (en) Sars-cov-2 main protease inhibitors
EP0708085B1 (fr) Ethers antiviraux des isostères du substrat de l'aspartate-protéase
US9421237B2 (en) Tripeptide boronic acid or boronic ester, preparative method and use thereof
JPH0381256A (ja) レニン阻害剤
CZ20004450A3 (en) Amidine derivatives
NO854516L (no) Nye 5-amino-4-hydroksyvalerylderivater.
HU219915B (hu) Eljárás gyógyászatilag hatásos hidrazinszármazékok és ezeket tartalmazó gyógyszerkészítmények előállítására
HU202515B (en) Process for producing new forscholine derivatives and pharmaceutical compositions comprising such compounds
US12060333B2 (en) Aminocarbamoyl compounds for the treatment of viral infections
CA2092414A1 (fr) Derives n-(2-alkyl-3-mercaptoglutaryl)-amino-diazacycloalcanone et leur utilisation comme inhibiteurs de la collagenase
DE69314911T2 (de) Cis-epoxide Derivate, verwendbar als irreversible HIV-Protease Inhibitoren und Verfahren und Zwischenprodukte zu ihrer Herstellung
EP0538374A1 (fr) Inhibiteurs de proteases aspartiques
EP0594586A1 (fr) Inhibiteurs de protease de l'hiv (virus de l'immunodeficience humaine)
WO1993002674A1 (fr) Inhibiteurs de la protease du vih
IL118869A (en) Antimicrobial mixtures containing a - amino acids and cyclopentane - b - amino acids and pharmaceutical preparations containing them
JPH04275263A (ja) キラルα−アミノアルデヒドからの、ヒドロキシエステル、ヒドロキシアミド及びラクトン化合物の立体制御された製造法
EP0628035A1 (fr) Inhibiteurs de la protease retrovirale
WO2022265577A2 (fr) Modulateurs d'enzyme du coronavirus, leurs procédés de synthèse et leurs utilisations
WO1992015319A1 (fr) Agents inhibiteurs de protease de l'hiv
ES2203955T3 (es) 7-acilamino-3-(metilhidrazono)metil-cefalosporinas sustituidas antibacterianas y productos intermedios.
US5151521A (en) 1-aminoethyl phosphonic acid derivatives
JPH02501735A (ja) 新規化合物
US6797730B2 (en) Peptide deformylase inhibitors
EP0610431A1 (fr) Inhibiteurs de la protease de vih contenant de la guanidine
JPH0532602A (ja) ナフチルメチルアミン誘導体及びこれを含有するレニン阻害剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP 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

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase