EP0538383A1 - Inhibiteurs de proteases aspartiques - Google Patents

Inhibiteurs de proteases aspartiques

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Publication number
EP0538383A1
EP0538383A1 EP91913579A EP91913579A EP0538383A1 EP 0538383 A1 EP0538383 A1 EP 0538383A1 EP 91913579 A EP91913579 A EP 91913579A EP 91913579 A EP91913579 A EP 91913579A EP 0538383 A1 EP0538383 A1 EP 0538383A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
unsubstituted
compound
chlorine
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Withdrawn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
EP91913579A
Other languages
German (de)
English (en)
Other versions
EP0538383A4 (fr
Inventor
Geoffrey Bainbridge Dreyer
John Gerald Gleason
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
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Filing date
Publication date
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Publication of EP0538383A1 publication Critical patent/EP0538383A1/fr
Publication of EP0538383A4 publication Critical patent/EP0538383A4/xx
Withdrawn legal-status Critical Current

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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
    • C07K5/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07K5/021—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)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compounds which are inhibitors of aspartic proteases, particularly of retroviruses.
  • 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. 8£, 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 overwhelm J. Med. Chem.. 22, 1285-88 (1990); Sigal et al., Eur. Pat. Appl. No. 337714; Dreyer et al. Eur. Pat. Appl. No. 352000).
  • 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 compound 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.
  • DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention have the structure:
  • B is, independently, an ⁇ -amino acid chosen from the group: Ala, Asn, Cys, Tip,
  • R 3 -CO- wherein R 3 is: a) hydrogen, b) C ⁇ -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 4 , wherein R 4 is:
  • D 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 1 0)2 wherein RlO is, independently, H or -C4 alkyl; or d) a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl;
  • R8-W- wherein R ⁇ is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; 9) R9-W- wherein R9 is phenyl or naphthyl unsubstituted or substituted with one or more substituents R 4 ;
  • N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R 4 ; m) C2-C6 alkynyl, optionally substituted with one or more groups R ⁇ ; or n) C2-C6 alkenyl, optionally substituted with one or more groups R ⁇ ;
  • C2 symmetric peptide compounds wherein R and R 2 are C1-C6 alkyl or aralkyl and ⁇ l 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.
  • 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-dirnethylpropyl, 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, cyclopen
  • 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, teti ⁇ ydrof
  • any variable e.g., A, B, R , R 3 , ..., 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.
  • 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
  • the peptide moieties denoted by 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.
  • the selection of residues or end groups may be used to confer favorable biochemical or physico-chemical properties to the compound.
  • the use of 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.
  • Synthesis of compounds of the structure is achieved by aldol condensation of an amino-protected alpha-amino aldehyde, P NHCH(Rl)CHO, with an amino-protected alpha-amino ketone, P NHCH(R 2 )COCH3, wherein P 2 and P 3 are amino protecting groups,using lithium diisopropylamine (LDA) at low temperature as detailed in the Examples.
  • LDA lithium diisopropylamine
  • the resulting 3-hydroxyketone is reduced to the 1,3-diol by use of a hydride reducing agent such as Me4NHB(OAc)3 in CH3CN/HOAC (Evans and Chapman, Tetrahedron Let..
  • the amino-protected alpha- amino ketone, P 3 NHCH(R 2 )COCH3, is prepared by addition of MeLi or MeMgBr to the
  • the compounds of this invention are prepared by the solid phase technique of
  • Each amino acid or peptide is suitably protected as known in the peptide art.
  • the Boc- or carbobenzyloxy (Cbz) 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.
  • Excep for the Boc 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 th carboxy terminus and working toward the amino terminus of the peptide.
  • Solid phase synthesis is begun by covalently 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.
  • 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).
  • HOBT 1-hydroxybenzotriazole
  • DMAP dimethylamino pyridine
  • Other methods such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a protected Boc-amino acid, and subsequent reaction with the free amine of a protected amino acid, optionally in the presence of a
  • 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
  • isobutyl chloroformate to form the mixed anhydride, which is subsequently reacted with the free amine of a second protected amino acid or peptide.
  • 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 converted 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-NH2 and recombinant HIV protease as in Strickler, et al., Proteins. Q,
  • 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. Examples of 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.
  • compositions for parenteral administration may additionally be comprise 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 dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may als 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.
  • excipient 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 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 15 mg/kg. These dosage units may be administered one to ten times daily for acute or chronic infection. Combination therapy as described in Eur. Pat. Appl. No. 337714 at pages 42-47 are included herein.
  • MENDT buffer 50 mM Mes (pH 6.0; 2-(N- morpholino) ethanesulfonic acid), 1
  • 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/ ⁇ 2 ⁇ - .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/ ⁇ 2 ⁇ - .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 l ⁇ M.

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Abstract

Composés utilisés comme inhibiteurs de protéases rétrovirales caractérisées par la formule (I) dans laquelle les groupes X1 et X2 peuvent être constitués de 0 à 2 groupes d'acides aminés substitués en fin de chaîne par de l'hydrogène ou par l'un parmi un certain nombre de groupes terminaux et le groupe R1 et R2 peut être sélectionné parmi un large éventail de radicaux d'hydrocarbure. On vise à obtenir des composés présentant une constante Ki d'inhibition de l'activité des protéases inférieure à 50 muM.
EP91913579A 1990-07-06 1991-07-03 Inhibiteurs de proteases aspartiques Withdrawn EP0538383A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54945890A 1990-07-06 1990-07-06
US549458 1990-07-06

Publications (2)

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EP0538383A1 true EP0538383A1 (fr) 1993-04-28
EP0538383A4 EP0538383A4 (fr) 1994-04-13

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EP91913579A Withdrawn EP0538383A1 (fr) 1990-07-06 1991-07-03 Inhibiteurs de proteases aspartiques

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EP (1) EP0538383A1 (fr)
JP (1) JPH05508851A (fr)
AU (1) AU8231391A (fr)
IE (1) IE912381A1 (fr)
MX (1) MX9100121A (fr)
PT (1) PT98229A (fr)
WO (1) WO1992000956A1 (fr)
ZA (1) ZA915270B (fr)

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No further relevant documents disclosed *
See also references of WO9200956A1 *

Also Published As

Publication number Publication date
PT98229A (pt) 1992-05-29
ZA915270B (en) 1992-07-29
IE912381A1 (en) 1992-01-15
MX9100121A (es) 1992-02-28
JPH05508851A (ja) 1993-12-09
AU8231391A (en) 1992-02-04
WO1992000956A1 (fr) 1992-01-23
EP0538383A4 (fr) 1994-04-13

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