WO1993017003A1 - Inhibiteurs de la protease retrovirale - Google Patents

Inhibiteurs de la protease retrovirale Download PDF

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Publication number
WO1993017003A1
WO1993017003A1 PCT/US1993/001785 US9301785W WO9317003A1 WO 1993017003 A1 WO1993017003 A1 WO 1993017003A1 US 9301785 W US9301785 W US 9301785W WO 9317003 A1 WO9317003 A1 WO 9317003A1
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alkyl
amino
phenyl
methyl
formula
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PCT/US1993/001785
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English (en)
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Geoffrey Bainbridge Dreyer
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Smithkline Beecham Corporation
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Priority to JP5515105A priority Critical patent/JPH07504417A/ja
Priority to EP93906262A priority patent/EP0628035A4/fr
Publication of WO1993017003A1 publication Critical patent/WO1993017003A1/fr

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    • 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
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • 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
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • This invention relates to retroviral protease inhibitor compounds, pharmaceutical compositions thereof, and a method of treating retroviral diseases therewith, including a metho of treating disease states associated with human
  • HIV-1 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
  • Such compounds are useful for inhibiting viral replication by inactivation of the protease.
  • the incorporation of heterocyclic elements in the P3' and P4' substrate positions of compounds containing a dipeptide isostere has been disclosed by deSolms et al . , J. Med. Chem., 34, 2852 (1991).
  • these compounds can be less than desirable for obtaining optimal drug delivery in mammalian organisms, particularly in humans.
  • Some of these compounds can also have a less than desirable serum half-life, and therefore duration of action, because they contain amide bonds in relatively high proportion, and thus are prone to metabolic degradation, hepatic clearance,, or other
  • the present invention provides compounds, hereinafter represented as formula (I), which bind to retroviral
  • proteases are inhibitors of retroviral proteases and are useful for treating diseases related to infection by retroviruses.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the present invention additionally provides a method for treating retroviral disease, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I).
  • R 1 and R 3 are each independently Q, Q-C 1-6 alkyl
  • Q is H, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, Ar or Het
  • R 2 is H or OH
  • R 4 is R 6 -NR 11 - or CONR 11 CHR 6 R 7 ;
  • R 5 is R 6 -NR 11 - or R 10 -NR 11 -;
  • R 6 is , or ;
  • X is NR 11 , O or S
  • R 7 is Q, Q-C 1-6 alkyl or Q-C 2-6 alkenyl
  • R 9 and R 11 are H or C 1-4 alkyl
  • R 10 is A- (B) n -;
  • R 12 is R 7 , OR 7 , NR 7 R 11 or an amino acid or amino alcohol
  • B is an amino acid
  • A is H, Ar, Het, R 17 (R 18 R 19 C) m , Ar-W, Het-W or
  • R 17 (R 18 R 19 C) m -W, or phthaloyl each optionally substituted by one to three groups chosen from R 15 or C 1-6 alkyl-R 15 ;
  • R 16 is H or C 1-6 alkyl
  • R 17 , R 18 and R 19 are independently: i) H, R 15 or
  • R 17 is as above and (R 18 R 19 C) are joined together to form a phenyl, naphthyl, C 3-6 cycloalkyl or Het ring, or iii) R 17 is as above and R 18 and R 19 together are
  • R 22 is H, C 1-6 alkyl, phenyl or phenyl-C 1-4 alkyl;
  • R 23 is -X'-(CH 2 ) q NR 24 R 25 , X" [((CH 2 ) r O) s ]R 26 ,
  • 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 24 and R 25 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 1 is H or C 1-4 alkyl
  • U is NR' or 0;
  • R 27 is C 1-6 alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, C 1-3 alkoxy, CONR' 2 , NR' 2 , CO 2 R', SO 2 NR' 2 , CH 2 NR 2 , NR'COR', NR'SO 2 R', X"[(CH 2 ) r O] s R' or CH 2 X"[(CH 2 ) r O] s R';
  • R 28 is H, C 1-6 alkyl or together with R 27 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
  • n 1-4;
  • n 0 or 1
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • nonracemic stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule. Such compounds may occur as pure enantiomers or diastereomers or as a mixture of individual stereoisomers.
  • the definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • R 1 and R 3 are C 1-6 alkyl, Ar-C 1-6 alkyl,
  • Ar-C 2-6 alkenyl, Ar-C 2-6 alkynyl, C 1-6 alkyl optionally
  • R 1 is benzyl and R 3 is phenylpropenyl or benzyl.
  • R 2 is H or OH.
  • R 2 is H.
  • R 4 is C0NR 11 CHR 6 R 7 .
  • R 5 is R 10 -NR 11 .
  • R 5 is
  • R5 is t-butyloxycarbonylamino or isopropyloxycarbonylamino.
  • R 6 is triazole.
  • R 7 is C 1-6 alkyl. Isopropyl is most preferred.
  • R 8 is H, C 1-6 alkyl, NH 2 , NO 2 or COR 12 .
  • R 8 is H.
  • R 9 is H.
  • B is Ala or Val.
  • m is 0 and B is absent.
  • R 23 is hydroxy-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy or -O(CH 2 ) 2 NR 24 R 25 , wherein R 24 and R 25 are are a 5- or 6- membered heterocycle, such as morpholino.
  • Representative compounds of this invention are:
  • a preferred compound is (2R,4S,5S,1'S)-6-phenyl-5-(t-butyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-(1,2,4-triazol-3-yl))methyl-2-phenylmethyl-hexanamide;
  • alkyl refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms.
  • C 1-4 alkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl. sec-butyl, tert-butyl;
  • C 1-6 alkyl includes additionally pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 2-ethylpropyl, neopentyl, n-hexyl 2,2-dimethylbutyl, 2-methylpentyl, and the like.
  • Alkoxy refers to an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom.
  • Alkylthio refers to an alkyl group of the indicated number of carbon atoms attached through a bridging sulfur atom.
  • Alkenyl refers to a straight or branched hydrocarbon chain of the indicated number of carbon atoms, which contains one or more carbon-carbon double bonds at any stable point along the chain, such as ethenyl, propenyl, butenyl,
  • Alkynyl refers to a straight or branched hydrocarbon chain of the indicated number of carbon atoms which contains a carbon-carbon triple bond at any stable point along the chain, such as ethynyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-methyl-3- ⁇ ropynyl, hexynyl and the like.
  • Cycloalkyl refers to a saturated ring group of the indicated number of carbon atoms.
  • C 3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
  • Cycloalkenyl refers to a saturated ring group of the indicated number of carbon atoms, having at least one endocyclic carbon-carbon double bond.
  • C 5-7 cycloalkenyl includes eyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Aryl refers to phenyl or naphthyl, optionally substituted with one to three halo, OH, OR 10 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, CF 3 , amino, NO 2 , carboxy, C 1-4 alkylcarbonyl, aminocarbonyl,
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one to three halo, OH, alkyl, alkoxy, alkyl-Het, alkoxy-Het, alkyl-phenyl, alkoxy-phenyl.
  • 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,
  • amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem . , 158, 9 (1984).
  • lipophilic amino acids are preferred for the moiety B, for instance, Val, Ala, Leu and lie.
  • a linkage B-0 refers to an oxygen atom bonded to the carboxyl group of an amino acid
  • a B-N linkage indicates a nitrogen atom bonded to the carboxyl group of an amino acid, as in an amide bond.
  • Amino alcohol refers to an amino acid in which the carboxyl group has been reduced to a methylene hydroxy group.
  • Boc refers to the t-butoxycarbonyl radical.
  • Cbz refers to the carbobenzyloxy radical.
  • Bzl refers to the benyzl radical.
  • Ac refers to acetyl.
  • Ph refers to phenyl.
  • BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate.
  • DCC refers to dicyclohexylcarbodiimide.
  • DMAP refers to
  • DMSO dimethylsulfoxide
  • HOBT 1-hydroxybenzotriazole
  • NMM N-methylmorpholine
  • DTT dithiothreitol
  • EDTA is
  • ethylenediamine tetraacetic acid DIEA is diisopropyl ethylamine.
  • DBU is 1.8 diazobicyclo[5.4.0]undec-7-ene.
  • DMSO is dimethylsulfoxide.
  • DMF is dimethyl formamide; Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2,4-disulfide and THF is tetrahydrofuran.
  • HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.
  • R 4 is CO-NR'CHR 6 R 7 , R 5 is R 10 R 11 N-, and R 1 , R 2 , R 3 and R 6 are as defined in formula (I), are prepared by:
  • R 1 ' , R 2 ' , R 3 ' , R 5 ' , R 6 ' and R 7 ' are R 1 -R 7 , respectively, as defined for formula (I) with any reactive groups
  • Pr 1 is H or a hydroxyl protecting group, and L ' is OH or a leaving group; or
  • A' and B' are as defined in formula (I) with any reactive groups protected;
  • the coupling reactions may be accomplished by activating the substrate with a reactive functional group in situ or prior to the coupling reaction, such that it is reactive with an amino group.
  • acids may be converted to acid chlorides, bromides, activated esters or anhydrides, or by adding a coupling reagent.
  • Coupling agents are well known in the art for activating a functional group in situ . Exemplary of such agents are DCC and other carbodiimides, DMAPEC, BOP and PPA. These coupling agents may optionally be used with other reagents, such a HOBT, NMM and DMAP, which may
  • Suitable leaving groups, L' are those which are
  • an amino group such as bromo, chloro, a substituted acyl (eg. trifluoroacetyl, bromobenzoyl,
  • A is a substituted alkyl group, such as
  • R 17 (R 18 R 19 C) m , L' may be a bromo, chloro, iodo or an alkyl or aryl sulonate.
  • A-L' may be a carboxylic acid halide, activated ester or anhydride, or a carboxylic acid in the presence of a coupling agent. Methods for preparing such compounds are well known.
  • A-L' may be a chloro- or bromo-formate, or an activated carbonate.
  • Haloformates may be prepared by reacting the appropriate alcohol with phosgene or
  • Activated carbonates may be prepared by reacting the appropriate alcohol with a suitable carbonate such as bis (4-nitrophenyl) carbonate.
  • A-L' may be a sulfonyl halide which may be prepared from the corresponding sulfonic acid.
  • A-L' may be a halothioformate, which may be prepared from a carbonyldihalide and an appropriate mercaptan.
  • A-L' may be a phosphonyl halide, which may be prepared from the corresponding phosphonic acid.
  • the amino carboxamides are generally known or are prepared by methods well known in the art, for instance, by treating a suitably protected ⁇ -amino acid ester with ammonia. Reaction of the an ⁇ -amino carboxamide with a suitable carboxamide acetal or ketal yields an acyl amidino intermediate which may be further reacted in situ with hydrazine, or a substituted hydrazine, in the presence of an acid to yield the desired triazole.
  • N-benzyloxycarbonyl-alaninamide may be heated with dimethylformamide dimethylacetal to yield N-[(N-benzyloxycarbonyl)alanylj-formamidine; and further reacted with hydrazine and acetic acid to yield 1-benzyloxycarbonylamino-1-(1,3,4-trazol-2-yl)ethane.
  • Further modification of the triazole by alkylation may be accomplished by routine methods. For instance, the triazole may be treated with an alkyl halide. Subsequent removal of the amino protecting group yields a compound of formula (III).
  • Suitable ⁇ -amino nitriles may be prepared by routine procedures from ⁇ -amino carboxamides, such as by dehydration of the carboxamide with phosphorous pentachloride.
  • R 6 is as defined for formula (I) and R 7 ' is as defined for formula (I) with any reactive groups protected, are also a part of this invention.
  • R 7' is C 1-6 alkyl and more preferably C 3-6 alkyl.
  • R 6 is tetrazol-5-yl or 1,3,4-triazol-2-yl
  • Pr 2 is H- or an arylmethyloxycarbonyl or C 1-6 alkyloxy group.
  • Benzyloxycarbonyl wherein the phenyl group is optionally substituted with one to three halogen, methoxy, methylthio or C 1-4 alkyl groups, is representative of the
  • acetyl, benzyl 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
  • the benzyl group may be removed by catalytic hydrogenation.
  • 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.
  • the present invention includes pharmaceutically
  • Acid addition salts of the present 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,
  • cationic salts may be prepared.
  • the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation.
  • 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 the present invention selectively bind to retroviral proteases in the same manner as,the virally coded natural substrates of the proteases and compete with these substrates for protease. This competition serves to inhibit viral replication by blocking the formation of crucial viral proteins from polyprotein precursors by the protease, and hence, to inhibit disease progression in vivo .
  • sequences of the protease binding and peptide bond cleavage sites of various retroviruses appear to be highly conserved, an inhibitor is likely to be broadly active against more than one retrovirus.
  • DNA viruses which are dependant upon virally encoded proteases, such as the hepatitis virus, may also be susceptible to such treatment.
  • retroviral replication and are useful in treating mammals, particularly human patients, who are infected with
  • a human comprises internally administering (e. g. orally, parenterally, buccally, trans-dermally,
  • a compound of formula (I) preferably dispersed in a pharmaceutical carrier.
  • Dosage units of the active ingredient may be selected by procedures routine to one skilled in the art, and are generally in the range of 0.01-50 mg/kg. These dosage units may be administered one to ten times daily for acute or chronic infection. Preferably the compound is administered at a level of 1-10 mg/kg, two to four times daily. No unacceptable toxicological effects are indicated when compounds of this invention are administered in the above noted dosage range.
  • the present invention also provides a method of treating disease states associated with HIV infection or Acquired
  • Immune Deficiency Syndrome comprising administering an effective amount of a compound of formula (I), preferably dispersed in a pharmaceutical carrier.
  • Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of the present invention.
  • anti-viral agents 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 a preferred agent.
  • pharmaceutical compositions comprise an anti-viral agent, a protease
  • This invention is also a pharmaceutical formulation which comprises a compound of formula (I) and a
  • compositions of the compounds of the present 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, but a lipophilic carrier, such as propylene glycol optionally with an alcohol, may be more appropriate for compounds of this invention.
  • 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 ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral
  • compositions may be added to enhance or stabilize the
  • Liquid carriers include syrup, soy bean oil, peanut oil, olive oil, glycerin, saline, ethanol, and water.
  • Solubilizing agents such as dimethylsulfoxide, ethanol or formamide
  • Carriers such as oils, optionally with solubilizing excipients, are especially suitable.
  • 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 representative.
  • another aspect of this invention is a pharmaceutical composition comprising a compound of formula (I) and an oil.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Solubilizing agents, such as dimethylsulfoxide or formamide, may also be added.
  • 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
  • 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 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.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
  • the pharmacological activity of the compounds of this invention may be demonstrated by enzyme assays to determine the inhibitory activity of the retroviral protease, by in vitro cellular-based assays to determine the ability of the compounds to penetrate cells and inhibit viral replication, and by pharmacokinetic assays to determine oral
  • 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 compound of Example 7(a) showed a Ki of less than 2 ⁇ M.
  • T-lymphocytes trypan blue stained cells
  • tetrazolium salt XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide sodium salt), to its formazan dye.
  • the XTT assay allows determination of the 50% toxic concentration of compounds for the cell/virus system used.
  • Mass spectra were performed using fast atom bombardment (FAB) or electro-spray (ES) ionization. Melting points were taken on a Thomas-Hoover capillary melting point apparatus and are uncorrected.
  • J indicates the NMR coupling constant in Hertz.
  • Celite ® is filter aid composed of acid washed
  • Florisil ® is an activated magnesium silicate chromatographic support and is a registered trademark of Floridon Co., Pittsburgh, Pennsylvania. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
  • N-Benzyloxycarbonyl-valinamide (2.40 g, 9.6 mmol) and dimethylformamide dimethyl acetal (1.25 g, 10.5 mmol) was suspended in 5 mL of anhydrous DMF and heated to 90°C for 15 min, and allowed to cool to room temperature. 5mL of glacial acetic acid was added and stirred vigorously at room
  • Example 1(a) The compound of Example 1(a) (255 mg, 0.93 mmol) and 10% palladium on carbon (15 mg) was suspended in 25 mL of
  • Example 1(b) (265 mg, 1.89 mmol), and diiospropylethylamme (538 mg, 4.17 mmol), were stirred in 10 mL of CH 2 CI 2 for 24 h. The reaction mixture was washed with 10% NaHCO 3 ,
  • Example 1(c) The compound of Example 1(c) (945 mg, 1.45 mmol) was dissolved in 10 mL of anhydrous THF. Tetrabutylammonium fluoride 1.0 M solution in THF (8.74 mL, 8.74 mmol) was added and the reaction mixture was stirred overnight. The solvent was evaporated and the residue was redissolved in CH 2 CI 2 , washed with brine, water, separated, dried (MgSO 4 ) and evaporated to yield a colorless oil. The crude product was purified (silica gel) to yield of the title compound as a white foam (550 mg, 71%).
  • N,N-dimethylacetamide (57 mg, 0.65 mmol) was added to a solution of trimethyloxonium tetrafluoroborate (100 mg, 0.68 mmol) in methylene chloride (2 mL) and the reaction stirred for 30 min After this time the methylene chloride was removed by distillation in vacuo and anhydrous
  • reaction mixture heated to 90oC for 30 min, cooled to room temperature and treated with glacial acetic acid (2 mL) followed by hydrazine (21 mg, 0.65 mmol). The resultant solution was reheated to 90°C. After 2 hours, the reaction mixture was poured into ice water (25 mL) and extracted with chloroform (3 X 50 mL). The combined extracts were dried (sodium sulfate), filtered, and concentrated to afford a yellow oil. The oil was chromatographed (Silica; 5%
  • Example 2a The methyltriazole of Example 2a (23 mg, 0.08 mmol) in methanol (5 mL) was hydrogenated for 1 h at 25°C. (1 atm) in the presence of 10% palladium on charcoal (1 mg). After this time the mixture was filtered and the solution concentrated in vacuo to yield a colourless oil which was dissolved in methylene chloride (5 mL) and coupled to (2R,4S,5S)-2-benzyl-4-(t-butyldimethyl)siloxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoic acid (31 mg, 0.071 mmol) by the procedure of Example 1(c) to yield the title compound (43 mg, 81%).
  • Example 2(b) The compound of Example 2(b) (43 mg, 0.065 mmol) in THF (3 mL) was treated with a solution of tetrabutylammonium fluoride (1M, 250 ⁇ L). The solution was stirred for 12 h, then concentrated in vacuo Preparative HPLC (4%
  • N,N-dimethylformamide dimethylacetal (248 mg, 2.0 mmol) was added to a solution of benzyloxycarbonyl-valinamide (520 mg, 2.0 mmol) in anhydrous dimethylformamide (3 mL). The reaction mixture was heated to 90°C for 30 min, cooled to room temperature and treated with glacial acetic acid (2 mL) followed by N-methylhydrazine (97 mg, 3.0 mmol).
  • Example 3(a) The compound of Example 3(a) (100 mg, 0.35 mmol) in methanol (5 mL) was hydrogenated for 1.5 h at 25°C. (1 atm) in the presence of 10% palladium on charcoal (6 mg). After this time the mixture was filtered and the solution concentrated in vacuo to yield a colourless oil which was dissolved in methylene chloride (5 mL) and coupled to (2R,4S,5S)-2-benzyl-4-(t-butyldimethyl)siloxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoic acid (166.5 mg, 0.32 mmol) by the procedure of Example 1(c) to yield the title comopound (189 mg, 89%).
  • the titled compound (0.177 g, 58%) was prepared from (2R,4S,5S)-2-(1-phenylpropyn-3-yl)-4-(t-butyldimethyl)siloxy- 5-(t-butyloxycarbonyl)amino-6-phenylhexanoic acid (0.25 g) and the compound of Example 1 (b) by using the coupling procedure of Example 1(c).
  • Example la The tetrazole of Example la (110 mg, 0.35 mmol) in methanol (7.5 mL) was hydrogenated for 1 h at 25°C. (1 atm) in the presence of 10% palladium on charcoal (12 mg). After this time the mixture was filtered and the solution concentrated in vacuo to yield the free amine as a colourless oil (53 mg, 0.42 mmol, 99%) which was dissolved in methylene chloride (5 mL) and coupled to (2R,4S,5S)-2-benzyl-4-(t-butyldimethyl)siloxy-5-(t-butylcarbonyl)amino-6-phenylhexanoic acid (200 mg, 0.38 mmol) using the procedure of Example 1(c). Chromatography (silica gel, 3%
  • Example 6(b) The compound of Example 6(b) (160 mg, 0.25 mmol) in THF (2 mL) was treated with a solution of tetrabutylammonium fluoride (1M in THF, 1.25 mL). The solution was stirred for 12 h, and concentrated in vacuo . Preparative HPLC (silica gel, 5% methanol/methylene chloride) yielded the title compound (27 mg, 21%). 1 H.
  • a suitable dosage form for oral administration has been prepared by dissolving the peptide of Example 2 (312.5 mg) in dimethyl sulfoxide (1 mL) and diluting to a concentration of 12.5 mg/mL with soybean oil.
  • the liquid may be encapsulated in a suitable soft gelatin capsule for administration.
  • a suitable dosage form for intravenous administration has been 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.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne des composés, plus spécifiquement des analogues dipeptidiques qui se lient aux protéases rétrovirales. Ces composés sont des inhibiteurs de protéases rétrovirales et sont utiles dans le traitement de maladies relatives aux infections par rétrovirus.
PCT/US1993/001785 1992-02-26 1993-02-26 Inhibiteurs de la protease retrovirale WO1993017003A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5515105A JPH07504417A (ja) 1992-02-26 1993-02-26 レトロウイルスプロテアーゼ拮抗薬
EP93906262A EP0628035A4 (fr) 1992-02-26 1993-02-26 Inhibiteurs de la protease retrovirale.

Applications Claiming Priority (4)

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US84229592A 1992-02-26 1992-02-26
US84229992A 1992-02-26 1992-02-26
US07/842,299 1992-02-26
US07/842,295 1992-02-26

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JP (1) JPH07504417A (fr)
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995033464A2 (fr) * 1994-06-03 1995-12-14 G.D. Searle & Co. Combinaisons d'inhibiteurs de protease retrovirale
WO1998038167A1 (fr) 1997-02-26 1998-09-03 Pfizer Inc. Derives amines de l'acide heteroaryle-hexanoique, leur preparation, et leur utilisation comme inhibiteurs selectifs du mip-1 alpha par fixation a son recepteur ccr1
WO2001057023A1 (fr) * 2000-02-04 2001-08-09 Pfizer Products Inc. Derives de l'amide heterocyclique
WO2002002512A2 (fr) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes utiles pour traiter la maladie d'alzheimer
EP1498417A1 (fr) * 2000-02-04 2005-01-19 Pfizer Products Inc. Amides hétérocycliques
EP1666452A2 (fr) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Composés pour le traitement de la maladie d'Alzheimer
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3997551A (en) * 1970-12-30 1976-12-14 Argus Chemical Corporation 3-Salicylamido-s-triazoles
US4038406A (en) * 1972-09-26 1977-07-26 Bayer Aktiengesellschaft 1,2,4-triazole antimycotic compositions and use thereof
US4505919A (en) * 1982-10-09 1985-03-19 Pfizer Inc. Antifungal S-arylmethyl- and S-heterocyclylmethyl ethers of 2-aryl-3-mercapto-1-(1H-1,2,4-triazol-1-yl) propan-2-ols

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3997551A (en) * 1970-12-30 1976-12-14 Argus Chemical Corporation 3-Salicylamido-s-triazoles
US4038406A (en) * 1972-09-26 1977-07-26 Bayer Aktiengesellschaft 1,2,4-triazole antimycotic compositions and use thereof
US4505919A (en) * 1982-10-09 1985-03-19 Pfizer Inc. Antifungal S-arylmethyl- and S-heterocyclylmethyl ethers of 2-aryl-3-mercapto-1-(1H-1,2,4-triazol-1-yl) propan-2-ols

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0628035A4 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU696299B2 (en) * 1994-06-03 1998-09-03 G.D. Searle & Co. Retroviral protease inhibitor combinations
WO1995033464A3 (fr) * 1994-06-03 1996-01-04 Searle & Co Combinaisons d'inhibiteurs de protease retrovirale
WO1995033464A2 (fr) * 1994-06-03 1995-12-14 G.D. Searle & Co. Combinaisons d'inhibiteurs de protease retrovirale
AP1056A (en) * 1997-02-26 2002-04-05 Pfizer Novel hexanoic acid derivatives.
WO1998038167A1 (fr) 1997-02-26 1998-09-03 Pfizer Inc. Derives amines de l'acide heteroaryle-hexanoique, leur preparation, et leur utilisation comme inhibiteurs selectifs du mip-1 alpha par fixation a son recepteur ccr1
US6403587B1 (en) 1997-02-26 2002-06-11 Pfizer Inc. Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-α binding to its CCR 1 receptor
WO2001057023A1 (fr) * 2000-02-04 2001-08-09 Pfizer Products Inc. Derives de l'amide heterocyclique
US6689886B2 (en) 2000-02-04 2004-02-10 Pfizer Inc. Quinoxalinyl carboxylic acid derivatives
EP1498417A1 (fr) * 2000-02-04 2005-01-19 Pfizer Products Inc. Amides hétérocycliques
EA005320B1 (ru) * 2000-02-04 2005-02-24 Пфайзер Продактс Инк. Производные гетероциклического амида
WO2002002512A2 (fr) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes utiles pour traiter la maladie d'alzheimer
EP1666452A2 (fr) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Composés pour le traitement de la maladie d'Alzheimer
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds

Also Published As

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JPH07504417A (ja) 1995-05-18
EP0628035A1 (fr) 1994-12-14
EP0628035A4 (fr) 1995-03-29
AU3735793A (en) 1993-09-13

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