WO1993009132A1 - Inhibiteurs de la protease de vih contenant de la guanidine - Google Patents

Inhibiteurs de la protease de vih contenant de la guanidine Download PDF

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Publication number
WO1993009132A1
WO1993009132A1 PCT/US1992/009402 US9209402W WO9309132A1 WO 1993009132 A1 WO1993009132 A1 WO 1993009132A1 US 9209402 W US9209402 W US 9209402W WO 9309132 A1 WO9309132 A1 WO 9309132A1
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WIPO (PCT)
Prior art keywords
alkyl
amino
butyloxycarbonyl
hydroxy
guanidine
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PCT/US1992/009402
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English (en)
Inventor
John Gerald Gleason
Robert Thomas Lum
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Smithkline Beecham Corporation
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Priority to JP5508659A priority Critical patent/JPH07501056A/ja
Priority to EP92924217A priority patent/EP0610431A1/fr
Publication of WO1993009132A1 publication Critical patent/WO1993009132A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • This invention relates to 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
  • Virally-encoded proteases function in many retroviruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins.
  • 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. Virol . , 53, 899-907(1985) and Debouck et al . , Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987). Inhibition of retroviral protease, therefore, presents a method of therapy for retroviral disease.
  • 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 is R 7 , R 7 CO, R 7 OCO, R 7 OCH(R 8 )CO or A-NR'CH(R 5 )CO;
  • Z is O or N-R 2 , where R 2 is H, CN or R'CO; D 1 and D 2 are or are absent;
  • J 1 and J 2 are NH, CH 2 or O;
  • M is or ;
  • Q 1 , Q 2 and Q 3 are H, NH 2 or OH;
  • V is N or C
  • Y is N, O or S
  • R 3 and R 4 are H or C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, T, T-C 1-6 alkyl, T-C 2-6 alkenyl or T-C 3-7 cycloalkyl, optionally substituted with R 16 ;
  • T is Ar, Het or C 3-7 cycloalkyl
  • R 5 and R 6 are C 1-6 alkyl, (CHR')n-T or (CHR')p-U, where U is NR' 2 , SR', OR', imidazole or CONR'2;
  • R 7 and R 8 are independently H, C 1-6 alkyl, C 3-7 cycloalkyl, T-(CHR 13 ) m -, T-(CH 2 ) m CH(T) (CH 2 ) m ;
  • R 9 is O, S or (H,H);
  • R' is H, C 1-4 alkyl or CH 2 Ph;
  • k 0 or 1
  • n 0-6;
  • n 0-2;
  • p is 1-4;
  • A is H, or Ar, Het, R 10 (R 11 R 12 C) m , Ar-W, Het-W or
  • R 10 (R 11 R 12 C) m -W optionally substituted by one to three groups chosen from R 13 or C 1-6 alkyl-R 13 ;
  • R 10 , R 11 and R 12 are independently: i) H, R 13 or
  • R 14 is H or C 1-6 alkyl
  • R 15 is H, C 1-6 alkyl, phenyl or phenyl-C 1-4 alkyl;
  • R 16 is -X'-R', -X'-(CH 2 ) q NR 17 R 18 , X"[((CH 2 ) r O) s ]R 19 ,
  • s is 1-6 and r is 1-3 within each repeating unit s ;
  • X' is CH 2 , O, S or NH
  • X" is CH 2 , NR', O, S, SO or SO 2 ;
  • R 17 and R 18 are i) C 1-6 alkyl, optionally substituted by OH, C 1-3 alkoxy, or N(R') 2 , ii) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR, O, S, SO, SO 2 , said heterocycle optionally substituted with C 1-4 alkyl, iii) aromatic heterocycle, optionally substituted with
  • R" is H or C 1-4 alkyl
  • R 20 is C 1-6 alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, C 1-3 alkoxy, CONR' 2 , NR' 2 ,
  • R 21 is H, C 1-6 alkyl or together with R 20 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
  • Z is NH.
  • M is .
  • R 1 is H, R 7 CO or R 7 OCO.
  • R 7 is C 1-6 alkyl or Ar-CH 2 or Het-CH 2 .
  • R 1 is H, pyridylmethyloxycarbonyl,
  • R 3 and R 4 are C 1-6 alkyl, Ar-C 1-4 alkyl,
  • Ar-C 2-4 alkenyl or Ar-C 2-4 alkynyl optionally substituted by R 13 .
  • R 3 and R 4 are benzyl.
  • R 5 is C 1-6 alkyl and J 1 is NH.
  • D 1 is Ala.
  • D 1 and D 2 are absent.
  • R 6 is C 1-6 alkyl and J 2 is NH.
  • E is (S)-Val.
  • Q 1 is OH.
  • Q 2 or Q 3 is H.
  • Q 2 and Q 3 are both H.
  • A is H or R 10 (R 11 R 12 C) m -W, optionally
  • A is H, methyl, acetyl, benzoyl, butyloxycarbonyl, benzyloxycarbonyl, 3-quinolinylmethyl-oxycarbonyl or pyridinylmethyloxycarbonyl.
  • A is butyloxycarbonyl or benzyloxycarbonyl.
  • Representataive compounds of this invention are:
  • N-benzyloxycarbonyl N'-[(2R,4S,5S)-2-phenylmethyl-4-hydroxy)-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine;
  • N-methoxycarbonyl N'-[(2R,4S,5S)-2-phenylmethyl-4-hydroxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine; N-(4-pyridyl)methyloxycarbonyl, N'-[(2R,4S,5S)-2-phenylmethyl-4-hydroxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine;
  • N-benzyloxycarbonyl N'-[(2R,4S,5S)-2-propyl-4-hydroxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine.
  • Preferred compounds are N-benzyloxycarbonyl
  • pharmacokinetic properties are useful, in particular, for the treatment of infections by the human immunodeficiency virus.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo .
  • Ar or aryl, as applied herein, means phenyl or
  • alkoxycarbonylC 1-6 alkyl HetC 1-4 alkoxy, HetC 1-4 alkyl, OH, Cl, Br or I.
  • Het, or heteroaryl indicates a five membered ring containing 0-2 double bonds, or a six membered ring
  • each ring having 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,
  • Het ring may optionally be substituted on the carbon or heteroatom by one to three
  • phenylC 1-6 alkyl group substituted by one to three C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkthio, trifluoroalkyl, OH, F, Cl, Br or I groups.
  • C 3-7 cycloalkyl includes cyclopropyl, cyclobutyl,
  • the cycloalklyl ring may be optionally substituted by one to three C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkthio, trifluoroalkyl, guanidino, amidino, hydroxyC 1-4 alkyl, amino, mono- or di-C 1-4 alkylamino, carboxy, amino-C 1-4 alkyl, Cx- ⁇ alkoxycarbonyl, aminocarbonyl,
  • HetC 1-4 alkyl OH, Cl, Br or I.
  • C 1-4 alkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl.
  • C 1-6 alkyl includes, additionally, pentyl, isopentyl and hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, l-methylpentyl, 2-ethylbutyl, and l-ethylbutyl.
  • C 2-6 alkenyl as applied herein means C 2-6 alkyl wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C 2-6 alkenyl includes ethylenyl, propenyl, butenyl, pentenyl, hexenyl and the isomers thereof.
  • C 2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C 2-6 alkynyl includes acetylene, propyne, butyne, pentyne, hexyne, and the isomers thereof.
  • Ar-C 1-6 alkyl, Ar-C 2-6 alkenyl and Ar-C 1-6 alkynyl mean C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkynyl wherein a carbon-hydrogen bond is replaced by a carbon-Ar bond.
  • Het-C 1-6 alkyl, Het-C 2-6 alkenyl and Ar-C 1-6 alkynyl mean C 1-6 alkyl, C 2-6 alkenyl and C 1-6 alkynyl wherein a carbon-hydrogen bond is replaced by a carbon-Het bond.
  • Halogen indicates a fluorine, chlorine, bromine and iodine atom.
  • M* indicates a mono- or divalent alkaline or earth metal ion, such as potassium, sodium, lithium, calcium or
  • Azacycloalkyl indicates a C 3-7 cycloalkyl group wherein a carbon atom is replaced by a nitrogen atom, such as
  • Azabicyclo-C 7-11 cycloalkyl indicates a C 7-11 cycloalkyl group wherein one of the carbon atoms is replaced by a nitrogen atom.
  • C 7-11 cycloalkyl indicates a stable mono- or bi-cyclic ring of 7 to 11 carbon atoms, which may be saturated or unsaturated, and may be substituted with one to three C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkthio,
  • C 7-11 cycloalkyl includes cycloheptyl, cyclooctyl, tetralinyl, indanyl, phenyl and naphthyl.
  • Amino acid means the D- or L- isomer of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
  • D 1 and D 2 may be amino acids.
  • E may be amino acids.
  • lipophilic amino acids of the L-configuration are preferred, for instance, Ala and Val.
  • amino acid abbreviations follow the IUPAC-IUB Joint Commission on
  • E is an amino acid it is attached to the carbonyl of the isostere through its amino terminus.
  • Dx is an amino acid it is attached to the amino group of the isostere through its carboxyl terminus.
  • 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
  • DBU 1,8 diazobicyclo[5.4.0]undec-7-ene
  • DMSO dimethylsulfoxide
  • DMF dimethyl formamide
  • MeOH is methanol
  • pyr pyridine
  • DMAPEC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMAP 4-dimethylamino pyridine
  • DTT is dithiothreitol
  • HOBT N-hydroxy-benzotriazole
  • EDTA is ethylenediamine tetraacetic acid
  • DIEA diisopropyl ethylamine
  • Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
  • NMM is N-methylmorpholine
  • TBAF is tetrabutyl ammonium fluoride
  • THF
  • DCC refers to dicyclohexylcarbodiimide
  • BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • PPA refers to 1-propanephosphonic acid cyclic anhydride
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide.
  • A is as defined for formula (I) and L' is a leaving group, such as halogen or OH, and, if necessary, a coupling reagent if necessary, and optionally removing any protecting groups.
  • Coupling reagents which are used to couple an amino group with a carboxyl group are well known in the art, such as DCC and other carbodiimides, DMAPEC, BOP and PPA, and they may optionally be used with other reagents, such as HOBT, NMM and DMAP, which may facilitate the reaction.
  • Coupling reagents may be also be reagents which are used to convert a poor leaving group, such as OH, to an activated ester or a halogen.
  • Thionyl chloride or bromide, oxallyl chloride, or phosphorousoxychloride may be used to form a halogen leaving group; and nitrophenol, N-hydroxy-succinimide and HOBT may be used to form an activated ester.
  • Suitable protecting groups for the amino and hydroxyl group, and reagents for deprotecting these functional groups are disclosed in Greene et al . , PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Second Edition, John Wiley and Sons, New York, 1991. Deprotection indicates the removal of the protecting group and replacement with an hydrogen atom.
  • suitably substituted acetyl and silyl groups are useful for protecting the hydroxyl group.
  • the acetyl group is commonly removed by reacting the compound with a base, such as an alkali metal hydroxide, in a mixture of an alcohol and water.
  • the silyl group such as trimethyl silyl, dimethyl-t-butyl silyl, and t-butyl-diphenyl silyl may be removed by a
  • fluoride reagent such as a tetra-alkyl ammonium fluoride, or by acid hydrolyis.
  • Suitable protecting groups for the amino group are those disclosed by Greene et al . , as indicated previously.
  • the benzyloxycarbonyl and t-butoxycarbonyl groups are especially useful amino protecting groups. If the protecting group is not the desired group R 1 , the protecting group may be
  • amino group may be alkylated or acylated to append the desired group as described hereinafter.
  • the isostere adducts (IV) and (VII) are similarly prepared by coupling reactions to add the A-D 1 -D 2 - and -E moieties respectively. Methods for preparing the isostere
  • Compounds wherein Q 1 is amino may also be prepared from the corresponding 4-hydroxy intermediate by methods common in the art for converting a hydroxyl group into an amino group, such as by oxidation of the hydroxyl group, and subsequent reductive amination.
  • the alcohol may be oxidized via the Swern method, with DMSO, trifluoroacetic anhydride and triethylamine in methylene chloride solution, and the corresponding ketone reduced with sodium cyanoborohydride and ammonium bromide in an alcohol/water solution.
  • heterocyclic ring is derived from the carboxyl group of the isostere (IX), previously described.
  • a hydroxyethylene isostere of formula (X) or (XI), above may be converted to a heterocycle via a thioamide, which may be prepared according to Scheme 2.
  • Typical halomethyl carbonyl reagents useful in the reaction are chloroacetaldehyde, iodoacetamide, methyl 3-bromopyruvate and the like. Hydrolysis or oxidation, as appropriate, yields the corresponding thiazole carboxylic acid.
  • the halomethyl carbonyl compounds, RCO-CH 2 -X, of this invention are commercially available or available by common synthetic methods.
  • Methyl 3-bromopyruvate is a suitable reagent for producing the 4-substituted imidazole, which may be hydrolyzed to yield a carboxylic acid.
  • hydroxyethylene isostere (X) is coupled to a 3-substituted- 4-amino-isoxazole (XXXI) to yield an acylaminoisoxazole
  • R 25 is a hydroxyl protecting group, such as the
  • a compound of formula (III) wherein W is NH and V is N is a triazole and is prepared according to Scheme 6.
  • Carboxamide (XXI), prepared as described in Scheme 2, is treated with a substituted dimethylamide dimethyl acetal (XL), wherein R 25 is a substituent which may be converted into a carboxylic acid, to yield the carboximidate (XLI).
  • the carboximidate is subsequently treated with hydrazine which, in the presence of an acid, cyclizes to yield the triazine ring. Conversion of the substituent R 25 to a carboxylic acid completes the preparation of a compound of formula (XIV) , wherein V and Y are nitrogen.
  • carboxylic acid may also be used with an appropriate coupling reagent.
  • an acid addition salt may be prepared.
  • 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,
  • methanesulfonic The acetate salt form is especially useful. If the final compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of 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 acceptable salts.
  • Certain of the compounds form inner salts or zwitterions which may also be acceptable.
  • the compounds of formula (I) are used in the manufacture of a medicament to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment.
  • the method of treatment comprises the
  • 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
  • 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
  • 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,
  • oils include any natural or synthetic non-ionic water-immiscible liquid, or low melting solid, which is capable of dissolving lipophilic compounds. Natural oils, such as triglycerides are
  • 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
  • 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
  • preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • a suitable dosage form for oral administration may be prepared by dissolving the peptide of Example 1 (312.5 mg) in dimethyl sulfoxide (1 mL) and diluting to a concentration of 12.5 mg/mL with soybean oil.
  • a suitable dosage form for intravenous administration may be prepared by dissolving the compound of Example 1 (0.02 g) in dimethyl sulfoxide (1 mL) and diluting to 20 mL with a 70% propylene glycol/30% ethanol solution. Dosing may be adjusted by varying the volume of administration or the initial quantity of drug dissolved in the carrier.
  • 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 are reverse transcriptase inhibitors and 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 1 to 1000 nM, preferably less than 100 nM.
  • the compound of Example 1 shows an IC 50 of less than 10 nM.
  • the ability of the compounds of this invention to inhibit the HIV-1 protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al . , Proc. Natl . Acad. Sci. , U.S.A. , 86, 9752 (1989), Grant et al . , Biochemistry, 30 8441 (1992), and EP-A 352 000.
  • the K i for the compounds of this invention are in the range of about 0.1 nM to about 2.5 ⁇ M.
  • Preferred compounds have Ki of less than 0.5 ⁇ M.
  • Preferred compounds have Ki of less than 1 nM.
  • IC50 for the compounds of this invention are in the range of about 1 nM to about 20 ⁇ M. Preferred compounds have IC50 of less than 20 nM.
  • RT indicates room temperature.
  • FAB indicates fast atom bombardment mass spectrometry.
  • ESMS indicates electrospray ionization mass spectrometry.
  • NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer.
  • Celite ® is filter aid composed of acid washed diatomaceous silica, and is a registered trademark of Mansville Corp., Denver,
  • ODS refers to an octadecylsilyl derivatized silica gel chromatographic support.
  • Microsorb is a silica gel packing made by Rainin Instruments Co, Woburn, Mass., having a nominal particle size of 5 ⁇ .
  • Zorbax is a silica gel or octadecylsilyl silica gel packing, having a nominal particle size of 5 ⁇ , manufactured by the DuPont Corp., Wilmington,
  • N-methyl piperidine (24.4 ml, 0.206 mol) was added via addition funnel to a stirring suspension of N,O- dimethylhydroxylamine hydrochloride (19.56 g, 0.2 mol) in methylene chloride (118 mL) at 0°C, forming a clear solution,
  • Boc-phenylalanine 53 g, 0.2 mol
  • THF 230 mL
  • methylene chloride 900 mL
  • Tetra-n-butylammonium bromide 160 mg, 0.5 mmol
  • KMnO 4 7.9 g, 50 mmol
  • the mixture was allowed to warm to room temperature with vigourous stirring and intermittent cooling. After 2 h, the thick black mixture was cooled to 0°C and saturated aqueous NaHSO 3 (75 mL) was added. After 15 min stirring, the resulting white mixture was filtered through Celite ® , the aqueous layer was separated and
  • hexamethyl-phosphoramide (0.285 mL, 1.64 mmol) was added to the solution. The solution was stirred for several min and allyl bromide (0.142 mL, 1.8 mmol) was added. After 2 h, the reaction mixture was quenched with a 10% solution of HCl and extracted with diethyl ether. The organic extracts were combined and evaporated to a clear oil. The oil was
  • the white foam was stirred in dimethylformamide (1.5 mL) at 25°C, and tert-butyl dimethylsilylchloride (0.407 g, 5 eq.) and imidazole (0.367 g, 10 eq.) were added.
  • the mixture was stirred under argon for 16 h, diluted with 10% aq. citric acid and extracted with diethyl ether. The combined organic extracts were washed with water, dried over magnesium
  • valine methyl ester hydrochloride (0.027 mL, 0.25 mmol) and valine methyl ester hydrochloride (.049 g, 0.183 mmol) were added. The mixture was warmed to 25°C and allowed to stir under argon for 14 h.
  • the mixture was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
  • the organic layer was dried over magnesium sulfate, filtered and evaporated to a semi-solid residue.
  • the residue was chromatographed (silica gel, dichloromethane:methanol) to give the title compound.
  • reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over K 2 CO 3 and concentratd to a colorless oil. This was chromatographed (silica gel, 3% Me0H/CH 2 Cl2) to afford the title compound as a white solid (0.032 g, 35%).
  • Example 7(a) The compound of Example 7(a) (65.0 mg, 0.115 mmol) was dissolved in MeOH (4.0 mL) and to this was added 0.18 mL of 2.5 N NaOH (18.4 mg, 0.46 mmol). The reaction mixture was stirred overnight at RT and concentrated to a white semi- solid. The semi-solid was redissolved in H 2 O, acidified to pH 3.5 with 3.0 NHCl, extracted into EtoAc, washed with saturated NaCl, dried over MgSO 4 , filtered and concentrated to a white solid (64.6 mg, 100%).
  • Example 7(b) The compound of Example 7(b) (64.6 mg, 0.117 mmol) was dissolved in dry DMF and successively treated with 1-hydroxybenzotriazole (19.0 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.7 mg, 0.117 mmol), carbobenzyloxyguanidine (22.6 mg, 0.117 mmol) and N,N-diisopropyl-ethylamine (15.1 mg, 0.117 mmol). The reaction mixture was stirred overnight at ambient
  • Example 7(c) The compound of Example 7(c) (70.2 mg, 0.097 mmol) was dissolved in THF (2.0 mL) and treated with tetrabutyl
  • N-benzyloxycarbonyl N'-[(2R,4S,5S)-2-propyl-4-hydroxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine; and N-benzyloxycarbonyl, N'-[(2R,4S,5S)-2-propyl-4-hydroxy-5- (t.-butyloxvcarbonyl)amino-6-phenylhexanoyl-(R)-valyl]- guanidine a) (2R,4S,5S)-2-propyl-4-hydroxy-5-(t-butyloxycarbonyl)amino- 6-phenylhexanoyl-(S)-valine methyl ester
  • Example 8(b) The compound of Example 8(b) (29.5 mg, 0.05 mmol) was dissolved in dry DMF and successively treated with 1-hydroxybenzotriazole (8.1 mg, 0.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 mg, 0.05 mmol), carbobenzyloxyguanidine (9.7 mg, 0.05 mmol), and N,N-diisopropylethylamine (6.5 mg, 0.05 mmol). The reaction was stirred overnight at ambient temperature under argon. DMF was removed in vacuo and the residue was
  • Example 8(c) The compound of Example 8(c) (25.0 mg, 0.033 mmol) was dissolved in THF (1.5 mL) and treated with 1.5 mL of 1.0 M tetrabutylammonium fluoride (392.0 mg, 1.5 mmol). The reaction mixture was stirred at ambient temperature overnight under argon. The mixture was diluted with EtoAc, washed with 5% NaHCO 3 , H 2 O, and saturated NaCl, dried over MgSO 4 , filtered, and concentrated to a tan solid. The solid was purified by flash chromatography (silica gel, 4% CH 3 OH/CH 2 CI 2 ) to yield the title diastereomers as pure compounds.
  • 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 filtered 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

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Abstract

L'invention concerne des composés de la formule (I) dans laquelle R1 et A représentent des groupes amino terminaux; Z représente O ou N-R2; M est un isostère dipeptidique; et D¿1? et D2 sont soit absents soit des acides aminés. Ces composés ainsi que leurs sels pharmaceutiquement acceptables sont des inhibiteurs puissants de la protéase du VIH-1 et sont utiles pour le traitement de maladies virales telles ques le syndrome d'immunodéfience acquise (SIDA).
PCT/US1992/009402 1991-11-01 1992-10-30 Inhibiteurs de la protease de vih contenant de la guanidine WO1993009132A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5508659A JPH07501056A (ja) 1991-11-01 1992-10-30 グアニジン含有ｈｉｖプロテアーゼ阻害剤
EP92924217A EP0610431A1 (fr) 1991-11-01 1992-10-30 Inhibiteurs de la protease de vih contenant de la guanidine

Applications Claiming Priority (2)

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US786,435 1985-10-11
US78643591A 1991-11-01 1991-11-01

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EP (1) EP0610431A1 (fr)
JP (1) JPH07501056A (fr)
AU (1) AU3069192A (fr)
MX (1) MX9206294A (fr)
PT (1) PT101026A (fr)
WO (1) WO1993009132A1 (fr)
ZA (1) ZA928396B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5430150A (en) * 1992-12-16 1995-07-04 American Cyanamid Company Retroviral protease inhibitors
US5455351A (en) * 1993-12-13 1995-10-03 Abbott Laboratories Retroviral protease inhibiting piperazine compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPM623994A0 (en) * 1994-06-15 1994-07-07 Biomolecular Research Institute Limited Antiviral dendrimers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337334A2 (fr) * 1988-04-14 1989-10-18 MERCK PATENT GmbH Dérivés d'acides aminés inhibant la rénine
EP0342325A2 (fr) * 1988-03-18 1989-11-23 MERCK PATENT GmbH Dérivés des acides aminés inhibant la rénine
EP0356223A2 (fr) * 1988-08-24 1990-02-28 Merck & Co. Inc. Inhibiteurs de HIV-protéase utiles pour le traitement du SIDA

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0342325A2 (fr) * 1988-03-18 1989-11-23 MERCK PATENT GmbH Dérivés des acides aminés inhibant la rénine
EP0337334A2 (fr) * 1988-04-14 1989-10-18 MERCK PATENT GmbH Dérivés d'acides aminés inhibant la rénine
EP0356223A2 (fr) * 1988-08-24 1990-02-28 Merck & Co. Inc. Inhibiteurs de HIV-protéase utiles pour le traitement du SIDA

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY vol. 28, no. 8, 1985, WASHINGTON, USA pages 1103 - 1106 TANG ET AL 'Optimization of the Schiff bases of N-hydroxy-N'-aminoguanidine as anticancer and antiviral agents' *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5430150A (en) * 1992-12-16 1995-07-04 American Cyanamid Company Retroviral protease inhibitors
US5455351A (en) * 1993-12-13 1995-10-03 Abbott Laboratories Retroviral protease inhibiting piperazine compounds

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ZA928396B (en) 1993-05-12
JPH07501056A (ja) 1995-02-02
PT101026A (pt) 1994-05-31
MX9206294A (es) 1993-08-01
AU3069192A (en) 1993-06-07
EP0610431A1 (fr) 1994-08-17

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