EP0594586A1 - Inhibiteurs de protease de l'hiv (virus de l'immunodeficience humaine) - Google Patents

Inhibiteurs de protease de l'hiv (virus de l'immunodeficience humaine)

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Publication number
EP0594586A1
EP0594586A1 EP91903689A EP91903689A EP0594586A1 EP 0594586 A1 EP0594586 A1 EP 0594586A1 EP 91903689 A EP91903689 A EP 91903689A EP 91903689 A EP91903689 A EP 91903689A EP 0594586 A1 EP0594586 A1 EP 0594586A1
Authority
EP
European Patent Office
Prior art keywords
amino
hydroxy
alanyl
oxo
benzyl
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Withdrawn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
EP91903689A
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German (de)
English (en)
Other versions
EP0594586A4 (en
Inventor
Geoffrey Bainbridge Dreyer
Thomas Joseph Carr
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
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SmithKline Beecham Corp
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Publication date
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Publication of EP0594586A1 publication Critical patent/EP0594586A1/fr
Publication of EP0594586A4 publication Critical patent/EP0594586A4/en
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • 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 MMV
  • mouse mammary tumor virus MMTV
  • feline leukemia virus FeLV
  • bovine leukemia virus BLV
  • Mason-Pfizer monkey virus MPMV
  • SSV simian sarcoma virus
  • SAIDS simian acquired immunodeficiency syndrome
  • the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.
  • the HTLV and HIV have been especially well characterized. Although diverse in detail, all retroviruses are rather similar in overall structure.
  • the extracellular virus particle is composed of an outer membrane studded with viral glycoproteins, a core of structural proteins, and a genome of single stranded ribonucleic acid.
  • the retroviral genome has a distinctive regional organization, referred to as the 5'- ⁇ a ⁇ -pol-env-3 ' structure, wherein the gag region encodes the core structural proteins, the pol region encodes certain critical viral enzymes such as reverse transcriptase, integrase and protease, and the env region encodes the envelope glycoproteins .
  • Viral replication occurs only within host cells and is dependent upon host cellular functions . Critical to this replication is the production of functional viral proteins. Protein synthesis is accomplished by translation of the open reading frames into polyprotein constructs, corresponding to the gag, pol and env reading frames, which are processed, at least in part, by a viral protease into the functional proteins.
  • 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., Virolo ⁇ v. 145, 280-92(1985), Crawford, et al. , £_. Virol . , 53, 899-907(1985) and Debouk, et al. , Proc. Na l. Acad. Sci. USA. 84, 8903-6(1987) . Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.
  • This invention comprises compounds, hereinafter, of the formula (I) , which inhibit the retroviral protease of HIV-1, and are useful for treating Acquired Immunodeficiency Syndrome (AIDS) .
  • AIDS Acquired Immunodeficiency Syndrome
  • This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
  • This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) .
  • A is BocNH, CbzNH, H, R'R"N, R"CONR*, or if a, b and c are 0 and Y is a covalent bond, then A is H, Boc, Cbz, R" or R"CO;
  • C and D are the same or different and are Ala, ⁇ -Ala, D-
  • X is Ala, lie, Leu, Val
  • Y is Ala, lie, Leu, Val or is a covalent bond
  • Z is CO2R"", CONR'R"", COR 1 , CH2OR”", CH2 ⁇ C(0)R” or H, or if e is 0 and Y is a covalent bond, Z is OR"" or NR'R""; b, c and e are each independently 0 or 1, provided that c and e are not simultaneously 0;
  • Rl is independently , C ⁇ _5 lk, C3_5alkenyl or benzyl;
  • R' and R" are H or C__5 lk
  • R" is H, C ⁇ -_5Al , C3_gcycloalkyl, (CH 2 ) n C6H5, (CH 2 ) n C5H4N, (CH 2 ) n OH, (CH 2 ) n NH2, or (CH 2 ) n NHC (NH)NH ; and pharmaceutically acceptable salts thereof; provided that if b and e are 0, Y is a covalent bond and D is Val, then Ri is not isobutyl.
  • the compounds of this invention are more potent than those reported previously and have favorable pharmaceutical properties.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • A comprises the terminal amino group of the peptide
  • Z comprises the terminal carboxyl group of the peptide.
  • the terminal residues of the peptide are "des-amino" and “descarboxy” amino acids respectively.
  • A comprises the terminal amino group of the residue C; or, when b is 0, to D.
  • the amino group of M is substituted by an acyl or alkyl group, as specially provided by A in formula (I) .
  • Z comprises the terminal carboxyl group of the amino acid residue corresponding to Y; or when Y is a covalent bond, to X.
  • Y is a covalent bond and d and e are 0, the terminal carboxyl group of M is substituted by Z as specially provided in formula (I) .
  • the amino terminus is on the left and the carboxy terminus is on the right.
  • all chiral amino acids (AA) are assumed to be of the L absolute configuration.
  • (4'R a )Phe refers to phenylalanine substituted in the 4 position of the phenyl ring by R a .
  • Boc refers to the t- butyloxycarbonyl radical
  • Cbz refers to the carbobenzyloxy radical
  • BrZ refers to ' the o-bromobenzyloxycarbonyl radical
  • Clz is the p-chlorocarbobenzyloxy radical
  • CI2Z refers to the 2,4-dichlorocarbobenzyloxy radical
  • Bzl refers to the benyzl radical
  • Ac refers to acetyl
  • Alk or C ⁇ -5Alk refers to C ] __5alkyl
  • Ph refers to phenyl
  • DCC refers to dicyclohexyl- carbodiimide
  • DMAP refers to dimethylaminopyridine
  • HOBT refers to 1-hydroxybenzotriazole
  • NMM is N-methylmorpholine
  • DTT is dithiothreitol
  • EDTA is ethylenediamine tetraacetic acid
  • HF hydrofluoric acid
  • TFA trifluoroacetic acid
  • C ⁇ _5al yl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl and isopentyl. As used herein in the compounds of this invention.
  • Especially preferred compounds of this invention are di-, tri- and tetrapeptides such as A-C-D-M-X-Y-Z, A-C-D-M-X-Z, A-C-D-M-Z, A-D-M-X-Y-Z, A-D-M-X-Z, A-D-M-Z and A-M-X-Y-Z.
  • X and Y are suitably valine.
  • C and D are suitably alanine.
  • C is Ala and X is Val.
  • Ri is H, Ci-5alkyl, allyl or benzyl. In one preferred embodiment Ri is H, C ⁇ _5alkyl, allyl or benzyl.
  • Ri is H, C ⁇ _5alkyl, allyl or benzyl.
  • i is propyl.
  • Z is CO2CH3,
  • Representative compounds of this invention are: (2R,4S,5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoyl-valyl valine methyl ester;
  • Other methods are disclosed by Holladay j ⁇ t. al ⁇ . J. Med. Chem.. 30, 374-83(1987) and Kempf, D., J. Qr ⁇ . Chem , 51, 21, 3921-26(1986) .
  • the amino acids or modified amino acids of this invention are generally available commercially or are prepared by conventional methods of organic chemistry. Solution synthesis of the peptides is accomplished using routine methods for coupling the appropriate amino acid residues and optionally removing any protective groups..
  • 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 1 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 1 dicyclohexyl carbodiimide (DCC)
  • catalysts such as 1- hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP) .
  • HOBT 1- hydroxybenzotriazole
  • DMAP dimethylamino pyridine
  • 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, DMAP or a trialkyl amine, with isobutyl chloroformate to form the "activated 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 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. Thus, ammonia or a substituted amine may be reacted with an activated acyl intermediate 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.
  • Carboxamides are preferred embodiments of this invention due their enhanced stability relative to esters . If the final peptide, after it has been deprotected, contains a basic group, an acid addition salt may be prepared.
  • Acid addition salts of the peptides are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
  • the acetate salt form is especially useful.
  • 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.
  • Cations such as Na + , K + , Ca ++ and NH4 " are examples of cations present in pharmaceutically acceptable salts .
  • Certain of the compounds form inner salts or zwitterions which may also be acceptable.
  • the compounds of formula (I) wherein M is -HNCHR; ] _R -, are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatmen .
  • the method of treatment comprises the administration orally, parenterally, buccally, trans-dermally, 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 generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection.
  • protease inhibiting properties of the peptides of this invention are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 0.1 nM to about 1.0 ⁇ M.
  • the following table is representative of the inhibition constants of these peptides.
  • compositions of the peptides 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. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • 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 peptides 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. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus.
  • 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
  • HAV human immunodeficiency virus
  • these peptides may be encapsulated, tableted or prepared in a emulsion or syrup for 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 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 g 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 peptides 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.
  • Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention.
  • anti-viral agents examples include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen.
  • Nucleoside analogues which include 2 ' ,3 '-dideoxycytidme (ddC) , 2 ' ,3 '-dideoxyadenine (ddA) and 3 '-azido-2 ' ,3 '-dideoxythymide (AZT) , are especially useful.
  • AZT is one preferred agent.
  • pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting peptide -of this invention and a pharmaceutically acceptable carrier.
  • the cells were lysed by sonication and insoluble material was removed by centrifugation at 15,000 x g av, for 15 mi .
  • the clarified supernatant was then brought to 40% of saturation with ammonium sulfate.
  • This suspension was stirred at room temperature for 30 min. and then centrifuged as above.
  • the resulting precipitate was redissolved/resuspended in a minimal volume of 20 mM Tris-HCl, pH 7.5; 200 mM NaCl; 0.1 mM each DTT and EDTA.
  • the sample was centrifuged again before application (in 5 ml aliquots) to a Beckman TSK G2000SW preparative HPLC gel filtration column (2.1 cm x 60 cm.) .
  • the column was equilibrated in the same buffer at a flow rate of 4 ml/min.
  • the effluent of the column was monitored at 280 nm and 1 min. fractions collected.
  • the rHIVPRT recombinant HIV protease
  • the protease was N85-95% pure.
  • By immunoblot analysis >90% of the immunoreactive material was precipitated at the ammonium sulfate step.
  • activity assay the highest peak of activity was found in the fractions collected at 45 and 46 minutes. Analysis of the TSK column fractions by RP- HPLC and SDS-PAGE indicated that the majority of the 11,000 Mr protein is also found in fractions 45 and 46.
  • the activity itself cannot be used to obtain reliable recovery data as it is influenced by high salt, i.e., with increasing salt, increasing levels of activity were obtained. Thus, with each step in the purification, more total activity was recovered than was started with.
  • the overall yield of rHIVPRT was Nl mg from a 50 gm E_ ⁇ _ coli cell pellet.
  • 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
  • N-methyl piperidine (24.4 ml, 0.206 mol) was added via addition funnel to a stirring suspension of N,0- dimethylhydroxylamine hydrochloride (19.56 g, 0.2 mol) in methylene chloride (118 ml) at 0°C, forming a clear solution
  • Boc-phenylalanine (53 g, 0.2 mol), THF (230 ml) and methylene chloride (900 ml) were combined and cooled to - 20°C, and N-methyl piperidine (24.4 ml) was added dropwise with stirring.
  • Methyl chloroformate (15.5 ml, 0.2 mol) was then added rapidly via addition funnel with good stirring, the temperature being maintained below -10°C.
  • the thick black mixture was cooled to 0°C and saturated aqueous NaHS ⁇ 3 (75 m l) was added. After 15 min stirring, the resulting white mixture was filtered through Celite®, the aqueous layer was separated and extracted with ether. The combined organic layers were washed with water and concentrated to a foam (6.9 g) .
  • the resulting crude 4-acetoxy acids were dissolved in 100 ml methanol and sodium methoxide (ca. 10 g) was added. The mixture was stirred at 25°C for two days then at 60°C for 18 hr. The thick mixture was concentrated, diluted with methylene chloride and extracted with 10% HCl. The aqueous layers were extracted twice with methylene chloride.
  • Example 1(e) To a solution of the lactone of Example 1(e) (.175 g, .507 mmol) in methanol (5 mL) was introduced 10% Pd on activated carbon (.020 g) . Hydrogen gas was bubbled through the solution for 1 hr and the solution was then maintained under a hydrogen atmosphere for 12 hr. The mixture was filtered through a pad of Celite with methanol and the solvents evaporated to give the titled compound as a white solid (.166 g, 94%) .
  • Example 1(f) The lactone of Example 1(f) (.166 g, .45 mmol) was dissolved in 1,4-dioxane (2 mL) and distilled water (1 mL) . To this cloudy solution was added 1 N NaOH (.523 mL, 1.1 eq.)
  • the white foam was stirred in dimethylformamide (1.5 L) at 25°C and to this solution was added tert-butyl dimethylsilylchloride (.407 g, 5 eq.) and imidazole (.367 g, 10 eq.) . The mixture was allowed to stir under an argon
  • step 1(e) substituting in step 1(e), in place of allyl bromide, either: (a) methyl iodide, (b) benzyl bromide, (c) methallyl bromide or (d) isobutyl bromide, the following compounds were prepared:
  • Example 1(g) To a solution of the acid of Example 1(g) (.080 g, .167 mmol) in tetrahydrofuran (1 mL) at -40°C under argon was added N-methyl morpholine (.027 mL, .25 mmol) and isobutyl chloroformate (.022 mL, .167 mmol) . After stirring for 15 min at -40°C, N-methyl orpholine (.027. mL, .00025 mole) and Valine valine methyl ester hydrochloride (.049 g, .183 mmol) were added. The mixture was warmed to 25°C and allowed to stir under argon for 14 hr.
  • the mixture was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
  • the organic layer was dried over magnesium sulfate, filtered and evaporated to a white semi-solid residue.
  • Example 4(a) The compound of Example 4(a) (.073 g, .106 mmol) was stirred in neat trifluoroacetic acid (1 mL) for 5 min, diluted with methanol, and treated with 2 drops of concentrated hydrochloric acid. The solvents were removed in vacuo to give the hydrochloride salt as a white foam(.071 g) .
  • the reaction was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
  • the organic layer was dried over magnesium sulfate, filtered,and evaporated to a white solid which was chromatographed (silica gel, 40:1 dichloromethane:methanol) to give the titled compound as a white solid (.020 g, 45%) .
  • Example 4(b) The compound of Example 4(b) (.020 g, .0251 mmol) was dissolved in 1 mL of neat trifluoroacetic acid and stirred for 10 min. The solution was diluted with dichloromethane and shaken with 5% aqueous sodium bicarbonate. The organic layer was removed and washed with water. The solvents were removed in vacuo and the resultant white solid was triturated with diethyl ether to give the titled compound as a white foam (.013 g, 76%) . NMR (DMSO-d 6 ) : ⁇ 8.18 (1H, d) , 7.61(1H, d) , 7.53 (1H, d) ,
  • Example 4 Using the procedure of Example 4, the carboxyl group of the compound of Example 3 was reacted with the hydrochloride of valinamide, the amino group was deprotected and acylated with Cbz-alanine, and the t-butyldimethylsilyl-protecting group was removed to yield the titled compound.
  • NMR (DMSO-d6) ⁇ 7.56(2H, dd) , 7.37(6H, m) , 7.20 (5H, m) , 6.98(1H, s) , 5.67(1H, m) , 5.05-4.88 (4H, m) , 4.09(2H, dd) ,
  • the carboxyl group of the compound of Example 2 (a) is reacted with the hydrochloride of valine methyl ester, valyl-valine methyl ester, valinamide, valyl-valinamide, valinol or valyl-valinol, the amino group is deprotected and acylated with Cbz-alanine, Cbz-alanyl- alanine, Cbm-alanine or propanoic acid, and the t- butyldimethylsilyl-protecting group is removed to yield the following specific compounds.
  • Valinols are acetylated in conventional fashion by treatment with triethylamine and acetic anhydride, acids are produced by hydrolysis with aq. methanolic potassium hydroxide of the corresponding methyl 5 esters. Carbobenzyloxy groups are removed by conventional hydrogenolysis with 5% palladium on carbon.
  • Phosphatidylcholine (1.4 g) and phosphatidylglycerol ( .6g) are dissolved in 300 ml of a 20% methanol in chloroform solvent and evaporated to dryness.
  • a solution of the peptide (30 mg in 200 ml of phosphate buffered saline) is added to the dry phospholipid film which is allowed to equilibrate at room temperature for 1-2 hr.
  • the liposome dispersion formed is then vortexed to insure uniform mixing.
  • the resulting suspension is extruded through a 0.2 ⁇ polycarbonate filter five times to produce a uniform size distribution. If necessary the suspension can be dialysed or ultracentrifuged to remove non-encapsulated peptide.
  • Phosphate buffered saline pH 7.4 is added in small aliquots with vortexing to achieve a concentration of 200 mg of liposomal gel per ml. Liposomes form spontaneously. This procedure produces 5 g of liposomal suspension. A standard dosage unit is 1 g of liposomal suspension.
  • a preparation which contains 25 mg of a peptide of this invention is prepared as follows: 25 mg of the peptide is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions in to a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume.
  • D5W dextrose in water
  • This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion.
  • a capsule for oral administration is prepared by mixing and milling 35 mg of the peptide with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.

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  • Virology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule: (I); où: A représente BocNH, CbzNH, H, R'R''N, R''CONR', ou , lorsque a, b et c ont la valeur 0 et Y est une liaison covalente, alors A représente H, Boc, Cbz, R'' ou R''CO; C et D sont identiques ou différents et représentent Ala, beta-Ala, D-Ala, Phe, Phg ou Val; X représente Ala, Ile, Leu, Val; Y représente Ala, Ile, Leu, Val ou une liaison covalente; Z représente Co2OR'''', CHONR'R'', COR', CH2OR'''', CH2OC(O)R'' ou H, ou, lorsque e est égal à 0 et Y est une liaison covalente, alors Z représente OR'''' ou NR'R''''; b, c et e ont chacun séparément la valeur 0 ou 1 à condition que c et e n'aient pas simultanément la valeur 0; M représente (alpha); où: R1 représente séparément AlkC1-5, un alcényle C3-5 ou un benzyle, R' et R'' représentent H ou AlkC1-5; R'''' représente H, AlkC1-5, un cycloalkyle C3-6, (CH2)nC6H5, (CH2)nC5H4N, (CH2)nOH, (CH2)nNH2, ou (CH2)nNHC(NH)NH2. Ces composés sont des inhibiteurs de la prothéase de l'HIV-1 et sont utiles dans le traitement du SIDA.
EP9191903689A 1990-01-09 1991-01-09 Hiv protease inhibitors Withdrawn EP0594586A4 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US469891 1983-02-25
US46266990A 1990-01-09 1990-01-09
US462669 1990-01-09
US46989190A 1990-01-23 1990-01-23
PCT/US1991/000178 WO1991010442A1 (fr) 1990-01-09 1991-01-09 Inhibiteurs de protease de l'hiv (virus de l'immunodeficience humaine)

Publications (2)

Publication Number Publication Date
EP0594586A1 true EP0594586A1 (fr) 1994-05-04
EP0594586A4 EP0594586A4 (en) 1994-08-17

Family

ID=27040413

Family Applications (1)

Application Number Title Priority Date Filing Date
EP9191903689A Withdrawn EP0594586A4 (en) 1990-01-09 1991-01-09 Hiv protease inhibitors

Country Status (3)

Country Link
EP (1) EP0594586A4 (fr)
JP (1) JPH05503703A (fr)
WO (1) WO1991010442A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2055685A1 (fr) * 1990-11-19 1992-05-20 Samuel L. Graham Inhibiteurs de la protease du vih ayant des substituts de polyether
US5436339A (en) * 1991-03-06 1995-07-25 Abbott Laboratories Process for the preparation of a substituted diaminoalcohol
JPH06510766A (ja) * 1991-09-11 1994-12-01 スミスクライン・ビーチャム・コーポレイション Ｈ．ｉ．ｖ．阻害剤としてのヘテロ環含有ペプチド同配体
DE4215874A1 (de) * 1992-05-14 1993-11-18 Bayer Ag Dithiolanylglycinhaltige HIV-Proteaseinhibitoren vom Hydroxyethylenisostertyp
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
ES2068739B1 (es) * 1993-01-21 1995-11-01 Smithkline Beecham Corp Inhibidores retrovirables de proteasas.
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
PT708085E (pt) * 1994-10-19 2002-11-29 Novartis Ag Eteres antivirais de isosteros de substrato de aspartato protease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337714A2 (fr) * 1988-04-12 1989-10-18 Merck & Co. Inc. Inhibiteurs de la protéase du HIV pour le traitement du SIDA
EP0352000A2 (fr) * 1988-07-08 1990-01-24 Smithkline Beecham Corporation Peptides liant des protéases rétrovirales
EP0386611A2 (fr) * 1989-03-06 1990-09-12 F. Hoffmann-La Roche Ag Dérivés d'acides aminés

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8322414D0 (en) * 1983-08-19 1983-09-21 Szelke M Renin inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337714A2 (fr) * 1988-04-12 1989-10-18 Merck & Co. Inc. Inhibiteurs de la protéase du HIV pour le traitement du SIDA
EP0352000A2 (fr) * 1988-07-08 1990-01-24 Smithkline Beecham Corporation Peptides liant des protéases rétrovirales
EP0386611A2 (fr) * 1989-03-06 1990-09-12 F. Hoffmann-La Roche Ag Dérivés d'acides aminés

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA. vol. 86 , December 1989 , WASHINGTON US pages 9752 - 9756 G.B.DREYER ET AL 'Inhibition of HIV 1 protease in vitro; Rational design of substrate analogue inhibitors' *
See also references of WO9110442A1 *

Also Published As

Publication number Publication date
WO1991010442A1 (fr) 1991-07-25
JPH05503703A (ja) 1993-06-17
EP0594586A4 (en) 1994-08-17

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