EP0538374A1 - Inhibitoren für asparagin-proteasen - Google Patents

Inhibitoren für asparagin-proteasen

Info

Publication number
EP0538374A1
EP0538374A1 EP91913442A EP91913442A EP0538374A1 EP 0538374 A1 EP0538374 A1 EP 0538374A1 EP 91913442 A EP91913442 A EP 91913442A EP 91913442 A EP91913442 A EP 91913442A EP 0538374 A1 EP0538374 A1 EP 0538374A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
phenyl
substituted
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91913442A
Other languages
English (en)
French (fr)
Other versions
EP0538374A4 (en
Inventor
Geoffrey Bainbridge Dreyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 Corp filed Critical SmithKline Beecham Corp
Publication of EP0538374A1 publication Critical patent/EP0538374A1/de
Publication of EP0538374A4 publication Critical patent/EP0538374A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals.
  • 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 feline leukemia virus
  • BLV bovine leukemia virus
  • MPMV Mason-Pfizer monkey virus
  • SSV simian sarcoma virus
  • SAIDS simian acquired immunodefic
  • HIV-1 protease has been classified as an aspartic acid protease (Meek et al., Proc. Natl. Acad. Sci. USA. 88, 1841 (1989)).
  • the proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus.
  • retroviruses which lack the 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), 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.
  • Inhibitors of recombinant HIV protease have been reported (Dreyer et al., Proc. Natl. Acad. Sci. USA. 86, 9752-56 (1989); Tomasselli et al. supra: Roberts et al., Science. 248. 358 (1990); Rich et al., J. Med. Chem.. 33, 1285-88 (1990); Sigal et al., Eur. Pat. Appl. No. 337 714; Dreyer et al. Eur. Pat. Appl. No. 352 000).
  • the limitations of current strategies for aspartic protease inhibition include (1) oral bioavailability; (2) plasma clearance lifetimes (e.g., through biliary excretion or degradation); (3) selectivity of inhibition; and (4) in the case of intracellular targets, membrane permeability or cellular uptake.
  • the present invention relates to a new inhibitors of retroviral and aspartic proteases. Unlike previously described inhibitors , the compounds of this invention are not analogues of peptide substrates possessing a scissile dipeptide mimetic. They also deviate substantially from peptide substrate-like structure in that they do not possess a conventional amino-to-carboxyl terminus orientation.
  • This invention comprises compounds having the structures particularly pointed out in the claims and described hereinafter which bind to retroviral proteases. These compounds are inhibitors of viral protease and are useful for treating disease related to infection by viruses.
  • This invention is also a pharmaceutical composition, which comprises an aforementioned compound and a pharmaceutically acceptable carrier therefor.
  • This invention further constitutes a method for treating viral diseases, which comprises administering to a mammal in need thereof an effective amount of an aforementioned inhibitor compound.
  • the compounds of this invention have the structure:
  • B is, independently, an ⁇ -amino acid chosen from the group: Ala, Asn, Cys, Tip, Gly, Gin, He, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A or the carboxy group of the adjacent residue B, whichever is appropriate, and the carboxy group of B is bonded to the amino group of the adjacent residue B or the structure, whichever is appropriate; and
  • R3-CO- wherein R 3 is: a) hydrogen, b) Cj-C ⁇ alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms, c) phenyl or naphthyl unsubstituted or substituted with one or more substituents R ⁇ , wherein R ⁇ is: O C1-C4 alkyl, ii) halogen, where halogen is F, Cl, Br or I, iii) hydroxyl, iv) nitro, v) C1-C3 alkoxy, or vi) -CO-N(R 10 )2 wherein R 10 is, independently, H or C1-C4 alkyl; or d) a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl;
  • R 5 (R 6 R 7 C)m-CO- wherein m 1-3 and R 5 , R 6 , and R 7 are independently: a) hydrogen, b) chlorine or fluorine, c) C1-C3 alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl, e) phenyl or naphthyl unsubstituted or substituted with one or more substituents R4, f) Ci - C3 alkoxy, g) a 5-7 member heterocycle, or h) R5, R , and R 7 may be independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is C3-C6 cycloalkyl;
  • R5(R6R7Qm W- wherein m 1-3 and W is OCO or SO 2 and R 5 , R 6 , and R 7 are as defined above, except R ⁇ , R6, and R 7 are not chlorine, fluorine or hydroxyl if they are adjacent to W; 8) R8-W- wherein R- is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl;
  • R9-W- wherein R ⁇ is phenyl or naphthyl unsubstituted or substituted with one or more substituents R ⁇ ;
  • R9-P(O)(ORH)-; R- and R 2 are the same or different and are: 1) -CH2R 12 wherein R 12 is a) NH-A wherein A is defined as above; b) R5-(R6R7Q -; c) R 5 -(R 6 R 7 C)m V- wherein V is O or NH, except R 5 , R 6 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) N(RlO) 2 , e) NR15R16 wherein R-5 and R - ⁇ are joined to form a 4-6 membered saturated nitrogens heterocycle including: i) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, f) R 17 OCH2 ⁇ wherein R 17 is: i) C -C 6 alkyl, ii) R9, or i
  • R- and R 2 are selected from C ⁇ -C alkyl, phenyl C j -Cg alkyl and C -Cg alkenyl.
  • R- and R 2 are benzyl.
  • X- and X 2 were selected from H, CbzVal, Val, Boc and Cbz.
  • R- ⁇ is hydrogen, methyl or CH O CR 19 wherein C 19 is Ci-C ⁇ alkyl.
  • the compounds of this invention are useful in the manufacture of a medicament, in particular, for a medicament for treating infection by retroviruses.
  • C 2 symmetric peptide compounds wherein R- and R 2 are C ⁇ -C(- alkyl or aralkyl and X- and X 2 are single amino acids or mono- or dipeptides; these groups may be terminally substituted by common acyl groups or blocking groups commonly used in peptide synthesis, such as t-Boc or Cbz, are also preferred.
  • Prodrugs are considered to be any covalently bonded carriers which release the parent drug.
  • compositions comprising a compound according to formula I and a pharmaceutically acceptable carrier.
  • alkyl refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like; "alkoxy” represents an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom; "cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; "
  • heterocycle represents a stable 5- to 7-membered mono- or 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.
  • heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, furyl, tetrahydrofuryl,t
  • any variable e.g., A, B, R*, R-, ..., R-7, heterocycle, substituted phenyl, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a geminal diol for example when R6 and R7 are simultaneously hydroxyl, is meant to be equivalent with a carbon-oxygen double bond.
  • Other abbreviations and symbols commonly used in the art used herein to describe the peptides include the following:
  • amino terminus is on the left and the carboxy terminus is on the right.
  • All chiral amino acids (AA) can occur as racemates, racemic mixtures, or individual enantiomers or diastereomers, with all isomeric forms being included in the present invention.
  • ⁇ -Ala refers to 3-amino propanoic acid.
  • Boc refers to the t-butyloxycarbonyl radical
  • Cbz or Z refers to the carbobenzyloxy radical
  • i-Bu refers to isobutyl
  • Ac refers to the acetyl
  • Ph refers to phenyl
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP refers to dimethylaminopyridine
  • HOBT refers to 1- hydroxybenzotriazole
  • NMM is N-methylmorpholine
  • DTT is dithiothreitol
  • EDTA is ethylenediamine tetraacetic acid
  • DIEA diisopropyl ethylamine
  • DBU is 1, 8 diazobicyclo [5.4.0] undec-7-ene
  • DMSO dimethylsulfoxide
  • DMF is dimethyl formamide
  • THF is tetrahydrofuran.
  • HF hydrofluoric acid
  • TFA trifluoroacetic acid
  • X - and X 2 are generally dipeptides or smaller. However, longer peptides which encompass the residues defined herein are also believed to be active and are considered within the scope of this invention.
  • residues or end groups may be used to confer favorable biochemical or physico-chemical properties to the compound.
  • hydrophilic residues may be used to confer desirable solubility properties or D-amino acids at the carboxy terminus may be used to confer resistance to exopeptidases.
  • Compounds represented by the structure I of the invention can be prepared as follows: Condensation of an amino-protected alpha-amino phosphonoyl chloride, P 2 NHCH(R 1 )PO(OR)Cl, wherein R is typically methyl or phenyl and P 2 is a protecting group such as Cbz, with the enolate of an ester, R 2 CH2CO2 100 where R 100 is an hydrocarbon group, such as methyl, t-butyl or benzyl, produces the intermediate
  • P 2 NHCH(R 1 )PO(OR)CH(R 2 )CO2R 1(X) The ester is deprotected by removal of the group R 100 and the resulting acid is subjected to Curtius rearrangement via its corresponding acyl azide (Shiori et al., J. Am. Chem Soc. 94, 6203 (1972)) to produce P 2 NHCH(R 1 )PO(OR)CH(R 2 )NHR 101 , where R l ⁇ l depends on the agent used to trap the intermediate isocyanate and is typically H, COCH2Ph, or CO(t-Bu).
  • R 1 , R 2 and R 18 are as defined for formula I, and P 2 and R 101 are H or amino- protecting groups.
  • Useful protecting groups are described in Greene, T.W., Protective Groups in Organic Synthesis. John Wiley & Sons, New York (1981), but many others are well known in the art. Boc and Cbz are typical amino protecting groups.
  • the amino-protected alpha-amino phosphonoyl chloride, P 2 NHCH(R 1 )PO(OR)Cl is prepared from the corresponding phosphonic diester, P 2 NHCH(R 1 )PO(OR)2, as described by Bartlett and Kezer, J. Am. Che . Soc. 106, 4282 (1984) and by Dreyer et al., European patent application EP 352 000.
  • the phosphonic diester, P 2 NHCH(R 1 )PO(OR)2 is prepared by condensation of benzyl carbamate with P(OPh)3 and the aldehyde R ⁇ CHO as described by Oleksyszyn et al., Synthesis.
  • Xl-Z wherein ⁇ l is defined as above for formula I, and Z is OH or a displaceable activating group, and optionally removing any protecting groups.
  • X 1 and X 2 are different, the coupling reactions are performed sequentially.
  • an amino-protecting group is maintained upon one amino group, while the other amino group is acylated, to arrive at a structure of the formula V,
  • this invention is also a process for preparing a compound of the formula I, which comprises reacting a compound of the formula V,
  • Suitable activating groups for carboxylic acids are acyl halides, such as an acid chloride or bromide, activated esters, such as the nitrophenyl esters or N-hydroxy-succinimide esters, activated anhydrides, such as isobutyl anhydride and the like.
  • Z may also be OH, or a carboxylic acid, when a suitable activating reagent, such as a carbodiimide or other coupling reagent, is used to effect the reaction (eg. the activation may occur in situ).
  • Activating groups for sulfonic acids are typically sulfonyl halides.
  • Activating groups for the alkyl group are groups such as the alkyl halide, alkyl sulfonate esters, for example mesylate, tosylate and brosylate, and alkyl acetates or benzoates. Other activating groups for these groups are well known and will be readily apparent to one skilled in the art depending upon the choice of X 1 .
  • Each amino acid or peptide is suitably protected as known in the peptide art.
  • the Boc- or carbobenzyloxy-group is preferred for protection of the amino group, especially at the ⁇ position.
  • a benzyl group or suitable substituted benzyl group is used to protect the mercapto group of cysteine, or other thiol containing amino acids; or the hydroxyl of serine or threonine.
  • the tosyl or nitro group may be used for protection of the guanidine of Arg or the imidazole of His, and a suitably substituted carbobenzyloxy group or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or the ⁇ -amino group of lysine.
  • Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group.
  • Cysteine and other sulfur-containing amino acids may also be protected by formation of a disulfide with a thioalkyl or thioaryl group.
  • the protective groups are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment as known in the art.
  • the peptide is built up sequentially starting from the carboxy terminus and working toward the amino terminus of the peptide.
  • Solid phase synthesis is begun by covalentiy attaching the C terminus of a protected amino acid to a suitable resin, such as a benzhydrylamine resin (BHA), methylbenzhydrylamine resin (MBHA) or chloromethyl resin (CMR), as is generally set forth in U.S. Patent No. 4,244,946.
  • BHA or MBHA support resin is used for the carboxy terminus of the product peptide is to be a carboxamide.
  • a CMR support is generally used for the carboxy terminus if the produced peptide is to be a carboxyl group, although this may also be used to produce a carboxamide or ester.
  • Modification of the terminal amino group of the peptide is accomplished by alkylation or acetylation as is generally known in the art. These modifications may be carried out upon the amino acid prior to incorporation into the peptide, or upon the peptide after it has been synthesized and the terminal amino group liberated, but before the protecting groups have been removed. Typically, acetylation is carried out upon the free amino group using the acyl halide, anhydride or activated ester, of the corresponding alkyl acid, in the presence of a tertiary amine.
  • Mono-alkylation is carried out most conveniently by reductive alkylation of the amino group with an appropriate aliphatic aldehyde or ketone in the presence of a mild reducing agent, such as lithium or sodium cyanoborohydride.
  • Dialkylation as well as quaternization may be carried by treating the amino group with an excess of an alkyl halide in the presence of a base.
  • Solution synthesis of peptides is accomplished using conventional methods used to form amide bonds.
  • a protected Boc-amino acid which has a free carboxyl group is coupled to a protected amino acid which has a free amino group using a suitable carbodiimide coupling agent, such as N, N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1 -hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP).
  • a suitable carbodiimide coupling agent such as N, N' dicyclohexyl carbodiimide (DCC)
  • catalysts such as 1 -hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP).
  • a protected Boc-amino acid or peptide is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran (THF), in the presence of a base, such as N-methyl morpholine, or a trialkyl amine, with isobutyl chloroformate to form the mixed anhydride, which is subsequently reacted with the free amine of a second protected amino acid or peptide.
  • anhydrous solvent such as methylene chloride or tetrahydrofuran (THF)
  • a base such as N-methyl morpholine, or a trialkyl amine
  • the peptide formed by these methods may be deprotected selectively, using conventional techniques, at the amino or carboxy terminus and coupled to other peptides or amino acids using similar techniques.
  • the protecting groups may be removed as hereinbefore described, such as by hydrogenation in the presence of a palladium or platinum catalyst, treatment with sodium in liquid ammonia, hydrofluoric acid, trifluoroacetic acid or alkali.
  • Esters are often used to protect the terminal carboxyl group of peptides in solution synthesis. They may be convened to carboxylic acids by treatment with an alkali metal hydroxide or carbonate, such as potassium hydroxide or sodium carbonate, in an aqueous alcoholic solution. The acids may be converted to other esters via an activated acyl intermediate as previously described.
  • the amides and substituted amides of this invention are prepared from carboxylic acids of the peptides in much the same manner.
  • ammonia or a substituted amine may be reacted with an activated acyl intermediate of an amino-protected ⁇ -amino acid or oligopeptide to produce the amide.
  • Use of coupling reagents, such as DCC, is convenient for forming substituted amides from the carboxylic acid itself and a suitable amine.
  • the methyl esters of this invention may be converted to the amides, or substituted-amides, directly by treatment with ammonia, or a substituted amine, in methanol solution.
  • a methanol solution of the methyl ester of the peptide is saturated with ammonia and stirred in a pressurized reactor to yield the simple carboxamide of the peptides.
  • Procedures for the determination of the inhibition constant (Ki) by Dixon analysis are described in the art, e.g., in Dreyer, et al. Proc. Natl. Acad. Sci. U.S.A.. 86, 9752-9756 (1989).
  • a peptidolytic assay is employed using the substrate Ac-Arg-Ala-Ser-Gln-Asn-Tyr- Pro-Val-Val-NH 2 and recombinant HIV protease as in Strickler, et al., Proteins. 6, 134-154
  • compositions of the compounds of this invention, or derivatives thereof may be formulated as solutions or lyophilized powders for parenteral administration.
  • 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.
  • a preferred composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier.
  • the liposome may be formed by dispersion of the compounds in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization.
  • a suitable method of making such compositions is more fully disclosed in copending Application Serial No. 06/763,484 and is incorporated herein by reference.
  • Such a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells.
  • an immunoglobulin or protein reactive with the viral particle or infected cells The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus.
  • An example of such a protein is the CD-4 T-cell glycoprotein, or a derivative thereof, such as sCD-4 (soluble CD- 4), which is reactive with the glycoprotein coat of the human immunodeficiency virus (HIV).
  • sCD-4 soluble CD- 4
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup or oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water.
  • Solid carriers include starch, lactose, calcium sulfate d ⁇ hydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glycerol monostearate or glycerol 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.
  • a liquid carrier 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 excipient 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.
  • This invention is also a method for treating viral infection, particularly infection by retroviruses, which comprises administering a compound of formula I to a patient infected with a susceptible virus. The method is particularly applicable to infection by the Human Immunodeficiency Virus, type 1.
  • the method of treatment comprises the administration orally, parenterally, bucally, trans-dermally, intravenously, intramuscularly, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier.
  • Dosage units of the active ingredient are selected from the range of 0.05 to 50 mg/kg of body weight. Dosage units will typically be from 50 to 1000 mg. These dosage units may be administered one to ten times daily for acute or chronic infection. The dosage will be readily determined by one skilled in the art and will depend upon the age, weight and condition of the patient, and the route of administration. Combination therapy as described in Eur. Pat. Appl. No. 337 714 at pages 42-47 are included herein.
  • step (b) the product of step (b) was added as a solution in 125 ml THF over 5 min.
  • the solution was stirred at -78 °C for 5 min then allowed to warm to ca. -10 °C over 30 min, after which excess 10% HC1 was added.
  • the mixture was extracted with ether, the organic layer was concentrated and the residue was purified by flash chromatography on 400 g silica (gradient: hexanes:ethyl acetate 4:1 (21), 1:1 (21), 1:2 (1.5 1)) to provide the titled compound as a mixture of isomers (12.23 g, 22.7 mmol, 67% yield).
  • 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 ⁇ - .1% TFA 915 min.), 20% acetonitrile/H2 ⁇ - .1% TFA (5 min) at 1.5 mL/min, detection at 220 nm.
  • reverse phase HPLC Beckman Ultrasphere ODS, 4.5 mm x 25 mm; mobile phase; 5-20% acetonitrile/H2 ⁇ - .1% TFA 915 min.
  • 20% acetonitrile/H2 ⁇ - .1% TFA 5 min at 1.5 mL/min, detection at 220 nm.
  • the compounds of this invention prefferably have Ki values less than 50 ⁇ M, preferably less than 10 ⁇ M and more preferably less than 1 ⁇ M.
  • Ki values less than 50 ⁇ M, preferably less than 10 ⁇ M and more preferably less than 1 ⁇ M.
  • the following are representative of the inhibitory activity of the compounds of this invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP19910913442 1990-07-06 1991-07-03 Aspartic protease inhibitors Withdrawn EP0538374A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54946090A 1990-07-06 1990-07-06
US549460 1990-07-06

Publications (2)

Publication Number Publication Date
EP0538374A1 true EP0538374A1 (de) 1993-04-28
EP0538374A4 EP0538374A4 (en) 1993-05-19

Family

ID=24193116

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910913442 Withdrawn EP0538374A4 (en) 1990-07-06 1991-07-03 Aspartic protease inhibitors

Country Status (4)

Country Link
EP (1) EP0538374A4 (de)
JP (1) JPH05508846A (de)
AU (1) AU8191091A (de)
WO (1) WO1992000954A1 (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
WO1993018006A1 (en) * 1992-03-11 1993-09-16 Narhex Limited Amine derivatives of oxo- and hydroxy-substitued hydrocarbons
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
DE69333270T2 (de) 1992-03-11 2004-08-05 Narhex Ltd. Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
US5321153A (en) * 1992-06-15 1994-06-14 Monsanto Company Process for making chiral alpha-amino phosphonates selected novel chiral alpha-amino phosphonates
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
DE4422911A1 (de) * 1994-06-30 1996-01-04 Hoechst Ag Phosphinsäure-Derivate, deren Herstellung sowie deren Verwendung
CA3183740A1 (en) 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0435059A1 (de) * 1989-12-16 1991-07-03 Hoechst Aktiengesellschaft Inhibitoren retroviraler Proteasen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH627477A5 (de) * 1977-02-10 1982-01-15 Ciba Geigy Ag Verfahren zur herstellung einer neuen phosphinsaeure und ihrer salze.
CH634968A5 (de) * 1977-04-01 1983-03-15 Ciba Geigy Ag Herbizides und pflanzenwuchsregulierendes mittel enthaltend eine neue phosphinsaeure oder deren salze, ester, amide oder hydrazide sowie verwendung derselben.
EP0209848A3 (de) * 1985-07-24 1988-07-27 Merck & Co. Inc. Enzyminhibitoren

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0435059A1 (de) * 1989-12-16 1991-07-03 Hoechst Aktiengesellschaft Inhibitoren retroviraler Proteasen

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY vol. 106, no. 15, 25 July 1984, WASHINGTON, DC US pages 4282 - 4283 PAUL A. BARTLETT 'Phosphinic Acid Dipeptide Analogues: Potent, Slow-Binding Inhibitors of Aspartic Pepsidases' *
See also references of WO9200954A1 *

Also Published As

Publication number Publication date
EP0538374A4 (en) 1993-05-19
WO1992000954A1 (en) 1992-01-23
AU8191091A (en) 1992-02-04
JPH05508846A (ja) 1993-12-09

Similar Documents

Publication Publication Date Title
WO1992000750A1 (en) Retroviral protease inhibitors
AU707283B2 (en) Antiviral ethers of aspartate protease substrate isosteres
CZ280292A3 (en) Novel derivatives of 5-amino-4-hydroxyhexanoic acid which derivatives act as therapeutic agents
EP0352000A2 (de) Retrovirale, Protease bindende Peptide
HU219915B (hu) Eljárás gyógyászatilag hatásos hidrazinszármazékok és ezeket tartalmazó gyógyszerkészítmények előállítására
WO1990000399A1 (en) Retroviral protease binding peptides
US5610146A (en) 2,3-disubstituted isoxazolidines, a process for their preparation, agents containing them, and their use
WO1992000948A1 (en) Inhibitors of retroviral proteases
US5643878A (en) 5-amino-4-hydroxyhexanoic acid derivatives
EP0538374A1 (de) Inhibitoren für asparagin-proteasen
EP2920182A1 (de) Makrocyclische verbindungen und verwendungen davon
WO1993001166A1 (en) 4-amino-3-hydroxycarboxylic acid derivatives
EP0538383A1 (de) Inhibitoren für asparagin-proteasen
AU770920C (en) Phenylalanine derivatives
WO1991010442A1 (en) Hiv protease inhibitors
AU678202B2 (en) Acyloxyhexanoic acid derivatives
EP0575500A1 (de) Hiv-proteaseinhibitoren
WO1993002674A1 (en) Hiv protease inhibitors
WO1999001470A2 (en) Peptidomimetic derivatives suicidal inhibitors of the hiv proliferation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930120

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

A4 Supplementary search report drawn up and despatched

Effective date: 19930330

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19950201