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WO1999053039A1 - Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine - Google Patents

Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine Download PDF

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Publication number
WO1999053039A1
WO1999053039A1 PCT/US1999/007723 US9907723W WO9953039A1 WO 1999053039 A1 WO1999053039 A1 WO 1999053039A1 US 9907723 W US9907723 W US 9907723W WO 9953039 A1 WO9953039 A1 WO 9953039A1
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Prior art keywords
ylcarbonyl
thiazol
hydrazide
leucinyl
leucinylamino
Prior art date
Application number
PCT/US1999/007723
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English (en)
Inventor
Scott Kevin Thompson
Daniel Frank Veber
Thaddeus Anthony Tomaszek
David Graham Tew
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Smithkline Beecham Corporation
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Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU34820/99A priority Critical patent/AU3482099A/en
Priority to CA002327282A priority patent/CA2327282A1/fr
Priority to HU0101513A priority patent/HUP0101513A2/hu
Priority to EP99916517A priority patent/EP1068304A4/fr
Priority to PL99343373A priority patent/PL343373A1/xx
Priority to JP2000543587A priority patent/JP2002511491A/ja
Priority to KR1020007011178A priority patent/KR20010042535A/ko
Priority to IL13862899A priority patent/IL138628A0/xx
Priority to BR9909530-0A priority patent/BR9909530A/pt
Publication of WO1999053039A1 publication Critical patent/WO1999053039A1/fr
Priority to NO20005032A priority patent/NO20005032L/no

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to methods, compounds and pharmaceutical 5 compositions for treating malaria.
  • the compositions comprise compounds which act as protease inhibitors which specifically inhibit cysteine proteases of the papain superfamily.
  • the compounds of the present invention are useful for treating diseases, particularly parasitic diseases, which are mediated by the activity of such proteases.
  • the present invention relates to treating malaria by inhibiting falcipain.
  • the Plasmodium falciparum parasite has a 48 hour life cycle within host erythrocytes that is responsible for all of the clinical manifestations of falciparum malaria. During this cycle, the erythrocyte is invaded by a merozoite, then the intracellular parasite develops from a ring stage into a more metabolically active trophozoite, divides asexually and becomes a schizont, and finally ruptures the host erythrocyte, releasing daughter
  • a selective inhibitor of falcipain may be an effective anti-malarial therapy either in conjunction with or as a replacement for the quinoline- derived drugs.
  • other parasites utilize cysteine proteases in their life cycle.
  • Trypanosoma cruzi Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi, Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus [onchocerciasis (river blindness)]
  • Brugia pahangi Entamoeba histolytica, Giardia lamblia, the helminths, Haemonchus contortus and Fasciola hepatica, as well as helminths of the genera Spirometra, Trichinella, Necator and Ascaris, and protozoa of the genera Cryptosporidium, Eimeria, Toxoplasma and Naegleria (McKerrow, J.
  • protease inhibitors most particularly inhibitors of falcipain, and these compounds are useful for treating diseases caused by cysteine proteases and particularly, malaria.
  • An object of the present invention is to provide protease inhibitors, such as inhibitors of cysteine proteases.
  • the present invention relates to compounds which inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily.
  • the compounds of the present invention are useful for treating diseases, particularly parasitic diseases, which may be therapeutically modified by altering the activity of such proteases.
  • the present invention relates to treating malaria by inhibiting falcipain.
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine proteases, with one or more of the following compounds: 2-[N-(N-benzyloxycarbonylglycinyl)]-2 -[N'-(N-benzyloxycarbonyl-L- leucinyl)]carbohydrazide;
  • proteases such as cysteine proteases
  • these compounds are used in the present method to treat diseases, in particular parasitic diseases, by inhibiting cysteine protease of the papain superfamily.
  • the present invention provides a method of treating malaria by the inhibition of falcipain with such compounds.
  • the present invention provides a method for treating diseases, particularly parasitic diseases, which may be therapeutically modified by altering the activity of cysteine proteases by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the following compounds:
  • the present method provides treatment of diseases, particularly parasitic diseases, by inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the above-listed compounds.
  • cysteine proteases Parasites known to utilize cysteine proteases in their life cycle include Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi, Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus [onchocerciasis (river blindness)] Brugia pahangi, Entamoeba histolytica, Giardia lambia, the helminths, Haemonchus contortus and Fasciola hepatica, as well as helminths of the genera Spirometra, Trichinella, Necator and Ascaris, and protozoa of the genera Cryptosporidium, Eimeria, Toxoplasma and Naegleria.
  • the present method provides treatment of diseases caused by infection by these parasites by inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the above-listed compounds.
  • the present invention provides a method of treating malaria, caused by infection with Plasmodium falciparum, by the inhibition of falcipain by administering a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the above-listed compounds.
  • the present method may be practiced by administering the above-listed compounds alone or in combination with other therapeutically effective compounds.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical.
  • the present invention includes all esters, hydrates, solvates, complexes and prodrugs of the above-listed compounds useful in the inventive method.
  • Prodrugs are any covalently bonded compounds which release the active parent drug in vivo.
  • a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • compounds may exist in tautomeric forms, such as keto-enol tautomers. each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, TCI, Sigma, Lancaster Synthesis, Bionet, Fluka, Maybridge or Bachem, and were used without further purification unless otherwise indicated. All solvents were purified by using standard methods readily known to those skilled in the art unless otherwise indicated. Starting materials are commercially available or were prepared by routine methods as can be found in standard reference books, such as the Compendium of Organic Synthetic Methods, Vol. I-IV (published by Wiley-Interscience). Coupling methods to form amide bonds herein are generally well-known to the art.
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
  • Acid addition salts of the above-listed compounds useful in the inventive method are prepared in a standard manner in a suitable solvent from the parent compound and an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic acid.
  • an acid such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic acid.
  • Optically active (R) and (S) isomers may be prepared using chiral synthons, chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds, it is intended to include both E and Z geometric isomers.
  • 5-Scheme 4 was treated with a carboxylic acid (such as thiophene-2-carboxylic acid, benzoxazole-5-carboxylic acid or 4-[2-(N,N- dimethylamino)ethyoxy]benzoic acid) and a peptide coupling reagent (such as EDC»HC1/1- HOBT, EDC'Mel/ 1-HOBT or HBTU) in an aprotic solvent (such as DMF) to provide 6 ⁇ Scheme 4.
  • a carboxylic acid such as thiophene-2-carboxylic acid, benzoxazole-5-carboxylic acid or 4-[2-(N,N- dimethylamino)ethyoxy]benzoic acid
  • a peptide coupling reagent such as EDC»HC1/1- HOBT, EDC'Mel/ 1-HOBT or HBTU
  • an aprotic solvent such as DMF
  • 6-Scheme 5 was treated with trifluoroacetic acid in dichloromethane to provide Scheme 5, which was treated with a carboxylic acid (such as pyrazinecarboxylic acid or 1- benzyl-5-methylimidazole-4-carboxylic acid) and a peptide coupling reagent (such as EDC»HCl/l-HOBT) in an aprotic solvent (such as DMF) to provide 8-Scheme 5.
  • a carboxylic acid such as pyrazinecarboxylic acid or 1- benzyl-5-methylimidazole-4-carboxylic acid
  • a peptide coupling reagent such as EDC»HCl/l-HOBT
  • aprotic solvent such as DMF
  • N- / -butoxycarbonyl amino acid, pivaloyl chloride and a tertiary amine base such as
  • 5-Scheme 6 which was treated with triflouroacetic acid in dichloromethane to provide 5-Scheme 6.
  • 5-Scheme 6 Treatment of 5-Scheme 6 with a carboxylic acid (such as 3-benzyloxybenzoic acid) and a peptide coupling reagent (such as EDC » HC1/ 1-HOBT, EDC»MeI/ 1-HOBT, HBTU or diethyl cyanophosphonate) in an aprotic solvent (such as DMF or dichloromethane) provided 6-Scheme 6, which was treated with Dess-Martin reagent in dichloromethane to provide 7-Scheme 6.
  • a carboxylic acid such as 3-benzyloxybenzoic acid
  • a peptide coupling reagent such as EDC » HC1/ 1-HOBT, EDC»MeI/ 1-HOBT, HBTU or diethyl cyanophosphonate
  • an aprotic solvent such as DMF or dichloromethane
  • R 3 CO was an N-tert- butoxycarbonyl-amino acid
  • 7-Scheme 7 was treated with trifluoroacetic acid in dichloromethane to provide 8-Scheme 7, which was treated with a carboxylic acid (such as 5-methyl-2-phenyloxazole-4-carboxylic acid, 7-methoxybenzofuran-2-carboxylic acid or 5- [2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid) and a peptide coupling reagent (such as EDC»HC1/ 1-HOBT) in an aprotic solvent (such as DMF) to provide 9z Scheme 7.
  • a carboxylic acid such as 5-methyl-2-phenyloxazole-4-carboxylic acid, 7-methoxybenzofuran-2-carboxylic acid or 5- [2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid
  • 5-Scheme 8 Treatment of 5-Scheme 8 with a carboxylic acid (such as 3-(2- pyridinyl)phenylacetic acid) and a peptide coupling reagent (such as EDC ⁇ C1/ 1-HOBT, EDC'Mel/ 1-HOBT or HBTU) in an aprotic solvent (such as DMF) provided 6-Scheme 8, which was treated with hydrogen gas in the presence of 10% palladium on carbon in ethanol to give 7-Scheme 8.
  • a carboxylic acid such as 3-(2- pyridinyl)phenylacetic acid
  • a peptide coupling reagent such as EDC ⁇ C1/ 1-HOBT, EDC'Mel/ 1-HOBT or HBTU
  • an aprotic solvent such as DMF
  • compositions which comprise one or more of the following compounds:
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be 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
  • -21- excipients such as polyvinylpyrrohdone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, manmtol, sodium chloride, or sodium citrate
  • these compounds may be encapsulated, tableted, or prepared in an 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
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stea ⁇ c acid, talc, pectin, acacia, agar or gelatin
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms, or milling, mixing and filling for hard gelatin capsule forms When a
  • the compounds of this invention may also 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 and molded into a suppository
  • an effective amount one or more of the above- listed compounds is administered to inhibit the protease implicated with a particular condition or disease
  • this dosage amount will further be modified according to the type of administration of the compound
  • parenteral administration of an effective amount of an inventive compound is preferred
  • An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients is most effective, although an intramuscular bolus injection is also useful
  • the parenteral dose will be about 0 01 to about 100 mg/kg, preferably between 0 1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit the prote
  • the compound may be administered in the form of a prodrug which, in general, is designed to enhance absorption and is cleaved in vivo to form the active component. Efficacious levels may also be achieved by administration of pharmaceutically active metabolites or bioisosteres of the compound.
  • Prodrugs of compounds of the present invention may be prepared by any suitable method.
  • the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit cysteine proteases, especially falcipain, or to achieve any other therapeutic indication as disclosed herein.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.1 to about 50 mg/kg given 1-2 times/day. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
  • an assay for determining Plasmodium falciparum cysteine protease catalytic activity and an assay to determine the amount of cysteine protease inhibition by a compound of the present invention are provided.
  • [AMC] v ss t + (vn - v ss ) [1 - exp (-k 0 b s t)] / k ⁇ bs ( 2 )
  • N-methylmorpholine (3.68 g, 36.4 mmol; 4.0 mL) and isobutyl chloroformate (2.37 g, 17.3 mmol; 2.25 mL).
  • ammonia was bubbled through the solution for 5 min.
  • the solution was warmed to room temperature, evaporated, and the residue was dissolved in ethyl acetate, washed with 0.1 N HCl, and saturated brine, then dried (MgS0 4 ), filtered and evaporated to dryness to give the title compound as a white solid (4.58 g, 100%).
  • Example 3(b) The compound of Example 3(b) (2.20 g, 7.83 mmol) was dissolved in acetone (35 mL), cooled to -10 °C, and ethyl bromopyruvate (1.68 g, 8.62 mmol, 1.08 mL) was added. After stirring for 1 hour, the solution was poured into methylene chloride/water, then into saturated aqueous NaHC0 3 . The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with saturated brine, dried (MgS0 4 ), filtered and concentrated.
  • Example 3(c) The compound of Example 3(c) (2.16 g, 5.73 mmol) was dissolved in ethanol (60 mL) and hydrazine hydrate (2.87 g, 57.3 mmol, 2.8 mL) was added and the solution was heated at 75 °C for 1 hour. The solution was cooled and evaporated to dryness to provide the title compound as a pale yellow foam (2.01 g, 97%).
  • Example 4(a) The compound of Example 4(a) (0.4 g, 1 mmol) was dissolved in DMF (4 mL) and N-methylmo ⁇ holine (0.3 g, 0.35 mL, 3 mmol) was added. The compound of Example 4(b) (0.28 g, 1 mmol) was then added and the reaction was allowed to stir for 4 hours. The reaction mixture was concentrated in vacuo, then chromatographed on silica gel to yield the title compound. MS (ESI): 584.2 (M+H)+.
  • Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 057 mmol) was added and heating at 85 °C was continued for 5 hours.
  • the mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 X 120 mL). The combined extracts were washed with saturated aqueous NaHC0 3 and saturated brine, dried (MgS0 4 ), filtered and concentrated. The residue was purified by flash chromatography on 180 grams of 230-400 mesh silica gel,
  • Example 1 1(a) A mixture of the compound of Example 1 1(a) (10 g, 77 mmol) and 10% palladium on carbon (1 g) in ethanol (150 mL) was stirred under an atmosphere of hydrogen (35 psi) for 12 hours. The mixture was filtered and treated with 100 ml of ethanolic HCl to afford, after evaporation under reduced pressure, the title compound as a brown solid (10.5 g, 97% yield), m.p. 132 °C.
  • Trimethylacetyl chloride (3.5 ml, 29 mmol) was added to a stirred solution of N- rf-butoxycarbonyl-L-leucine (7.3 g, 31 mmol) and N,N-diisopropylethylamine (9 ml, 52 mmol) in dichloromethane (200 mL). After 1 hour, the compound of Example 11(b) (4 g, 28 mmol) was added and the mixture was allowed to stir overnight. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with 0.5N HCl, saturated sodium bicarbonate and saturated brine, then dried (MgS0 4 ) and filtered.
  • Dess-Martin periodinane 500 mg, 1.2 mmol was added to a stirring solution of the compound of Example 1 1(g) (280 mg, 0.7 mmol) in dichloromethane (10 mL). After 1 hour, ether was added followed by sodium thiosulfate (570 mg, 3.6 mmol). After an additional 15 minutes the reaction was washed with saturated sodium bicarbonate and saturated brine, then dried (MgS0 4 ) and filtered. Evaporation of the solvent gave the title compound as a white foam (270 mg, 93%).
  • Example 12(a) The compound of Example 12(a) (14.0 g, 123 mmol) was dissolved in chloroform (100 mL) and benzoyl isothiocyanate (20 g, 123 mmol, 18 mL) was added. After stirring 45 minutes at room temperature, the solution was concentrated to provide the title compound as a yellow solid (29 g, 85%). MS (ESI): 257.1 (M+H)+.
  • Example 12(b) The compound of Example 12(b) (29 g, 105 mmol) was dissolved in methanol (100 mL) and water (100 mL), potassium carbonate (43 g, 315 mmol) was added and the solution was heated at reflux overnight. The reaction mixture was concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate, water and dried over
  • Example 13(c) The compound of Example 13(c) (1.68 g, 7.875 mmol) was added, followed by 1- hydroxybenzotriazole hydrate (1.276 g, 9.45 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide methiodide (1.81 g, 9.45 mmol), and the reaction was stirred an additional 12 hours. The reaction mixture was concentrated in vacuo, then chromatographed on silica gel to yield the title compound as a white solid (1.70 g, 43%). MS (ESI): 499.3 (M+H)+.
  • Example 14(b) The compouund of Example 14(b) (0.5, 1.9 mmol) was dissolved in MeOH (10 mL) and sodium borohydride (0.144 g, 3.8 mmol) was added at 10 °C and the reaction was allowed to stir for 15 minutes. The reaction was quenched with water (10 mL) and was extracted with EtOAc (25 mL). The combined organic extracts were dried (MgS0 4 ), filtered and concentrated to give the title compound which was used without further purification (0.5 g, 100%).
  • Example 14(c) The compound of Example 14(c) (0.5 g, 1.9 mmol) was dissolved in MeOH (7.5 mL) and triethylamine (0.72 g, 7.1 mmol, 1.0 mL), 1 ,3-propanedithiol (1.08 g, 10 mmol, 1.07 mL) was added and the reaction was allowed to stir overnight, concentrated in vacuo, then the white solid was washed with hexane providing the title compound which was used in the next reaction without further purification.
  • Example 13(c) (0.4 g, 1.9 mmol) were dissolved in DMF (15 mL), 1-hydroxybenzotriazole hydrate (0.27 g, 2 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (0.38 g, 2 mmol) were added, and the reaction mixture was allowed to stir overnight. The reaction was partitioned between EtOAc and 1 N NaOH, the combined organic layers were dried (MgS0 4 ), filtered and concentrated to give the title compound (0.33g, 40%). MS (ESI): 434.2 (M+H)+.
  • Example 14(f) The compound of Example 14(f) (0.28 g, 0.75 mmol) was dissolved in DMF (10 mL). HBTU (0.3 g, 0.8 mmol), N-tert-butoxycarbonyl-L-leucine (0.2 g, 0.8 mmol), N- methylmorpholine (0.34 g, 3.37 mmol, 0.37 mL) were added, and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated in vacuo, then chromatographed on silica gel to yield the title compound as a white solid. MS (ESI):
  • Example 14(g) The compound of Example 14(g) (2.0 g, 3.9 mmol) was dissolved in methylene chloride (140 mL) and 4 M HCl in dioxane (85 mL) and allowed to stir at room temperature for 2 hours. Toluene (100 mL) was added and the reaction mixture was concentrated in vacuo to give the title compound which was used in the following step without further purification: MS (ESI): 413.2 (M+H)+.

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Abstract

L'invention concerne des composés et des compositions pharmaceutiques qui inhibent les protéases, telles que les cystéine-protéases. Elle porte notamment sur des composés et des compositions pharmaceutiques qui inhibent les cystéine-protéases de la superfamille de la papaïne. Les composés et les compositions pharmaceutiques de l'invention sont utiles pour le traitement de maladies, en particulier de maladies parasitaires, induites par lesdites protéases. Elle se rapporte encore à une méthode de traitement de la malaria par l'inhibition de la cystéine-protéase appelée falcipaïne.
PCT/US1999/007723 1998-04-09 1999-04-08 Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine WO1999053039A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU34820/99A AU3482099A (en) 1998-04-09 1999-04-08 Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily
CA002327282A CA2327282A1 (fr) 1998-04-09 1999-04-08 Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine
HU0101513A HUP0101513A2 (hu) 1998-04-09 1999-04-08 Parazitikus betegségek kezelése a papain szupercsalád cisztein-proteázainak gátlásával
EP99916517A EP1068304A4 (fr) 1998-04-09 1999-04-08 Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine
PL99343373A PL343373A1 (en) 1998-04-09 1999-04-08 Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily
JP2000543587A JP2002511491A (ja) 1998-04-09 1999-04-08 パパインスーパーファミリーのシステインプロテアーゼの阻害による寄生虫病の治療
KR1020007011178A KR20010042535A (ko) 1998-04-09 1999-04-08 파파인 상과의 시스테인 프로테아제 저해에 의한 기생충질환의 치료
IL13862899A IL138628A0 (en) 1998-04-09 1999-04-08 Treatment of parasitic diseases by inhibition of cyteine proteases of the papain superfamily
BR9909530-0A BR9909530A (pt) 1999-04-08 1999-04-08 Tratamento de doenças parasitárias pela inibição das proteases de cisteìna da superfamìlia da papaìna
NO20005032A NO20005032L (no) 1998-04-09 2000-10-06 Behandling av parasittsykdommer ved inhibering av cysteinproteaser av papainsuperfamilien

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US8122198P 1998-04-09 1998-04-09
US60/081,221 1998-04-09

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US09673050 A-371-Of-International 2000-10-10
US10/120,720 Continuation US20020156018A1 (en) 1998-04-09 2002-04-12 Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily

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DZ (1) DZ2752A1 (fr)
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PL (1) PL343373A1 (fr)
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WO2000029408A1 (fr) * 1998-11-13 2000-05-25 Smithkline Beecham P.L.C. Inhibiteurs de morpholino-ethoxybenzofuran protease
EP1112741A1 (fr) * 1997-12-11 2001-07-04 Biovail Technologies Ltd Utilisaton d'inhibiteurs de protéases pour le traitement des infections nécrotisantes
WO2000016763A3 (fr) * 1998-09-21 2001-10-11 Univ Florida Agents antipaludeens
WO2002057248A3 (fr) * 2001-01-17 2002-10-03 Incenta Ltd Inhibiteurs de la cruzipain et autres cysteine proteases
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
WO2002088106A3 (fr) * 2000-11-17 2003-09-04 Medivir Ab Inhibiteurs de la cysteine protease
US6635784B2 (en) 2000-09-29 2003-10-21 Eastman Chemical Company Process for the preparation of enantiomerically-enriched cyclopropylalanine derivates
EP1067894A4 (fr) * 1998-05-21 2004-09-08 Smithkline Beecham Corp Inhibiteurs de protease
EP1488791A3 (fr) * 1998-09-21 2005-04-06 University Of Florida Research Foundation, Inc. Agents contre la malaria
US6958358B2 (en) 2001-01-17 2005-10-25 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
USRE39132E1 (en) 1998-08-31 2006-06-13 University Of Florida, Research Foundation, Inc. Thiazoline acid derivatives
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
WO2007012180A1 (fr) * 2005-07-26 2007-02-01 Merck Frosst Canada Ltd. Inhibiteurs de la cystéine protéase de la famille de la papaïne pour le traitement des maladies parasitaires
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US7425562B2 (en) 2001-01-17 2008-09-16 Amura Therapeutics Ltd. Inhibitors of cruzipain and other cysteine proteases
US8278458B2 (en) 2005-04-04 2012-10-02 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
US8324397B2 (en) 2007-03-15 2012-12-04 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
US8334256B2 (en) * 2003-06-18 2012-12-18 Tranzyme Pharma Inc. Pharmaceutical salts of macrocyclic modulators of the ghrelin receptor
EP2633855A1 (fr) 2012-03-01 2013-09-04 Veterinärmedizinische Universität Wien Inhibiteurs de la protéase pour le traitement d'infections par Trichomonas gallinae
US8604216B2 (en) 2003-09-09 2013-12-10 University Of Florida Research Foundation, Inc. Desferrithiocin derivatives and methods of use thereof
US8642799B2 (en) 2007-11-29 2014-02-04 Merck Canada Inc. Cysteine protease inhibitors for the treatment of parasitic diseases
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine
US8921521B2 (en) 2003-06-18 2014-12-30 Ocera Therapeutics, Inc. Macrocyclic modulators of the Ghrelin receptor
US10010535B2 (en) 2013-11-22 2018-07-03 University Of Florida Research Foundation, Incorporated Desferrithiocin analogs and uses thereof
US10570104B2 (en) 2015-04-27 2020-02-25 University Of Florida Research Foundation, Incorporated Metabolically programmed metal chelators and uses thereof
US11931346B2 (en) 2011-12-16 2024-03-19 University Of Florida Research Foundation, Incorporated Uses of 4′-desferrithiocin analogs

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Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1112741A1 (fr) * 1997-12-11 2001-07-04 Biovail Technologies Ltd Utilisaton d'inhibiteurs de protéases pour le traitement des infections nécrotisantes
JP2001187746A (ja) * 1997-12-11 2001-07-10 Biovail Technologies Ltd 壊死性感染症の治療
EP1067894A4 (fr) * 1998-05-21 2004-09-08 Smithkline Beecham Corp Inhibiteurs de protease
US7126004B2 (en) 1998-08-31 2006-10-24 University Of Florida Research Foundation, Inc. Thiazoline acid derivatives
US8008502B2 (en) 1998-08-31 2011-08-30 University Of Florida Research Foundation, Inc. Thiazoline acid derivatives
USRE39132E1 (en) 1998-08-31 2006-06-13 University Of Florida, Research Foundation, Inc. Thiazoline acid derivatives
WO2000016763A3 (fr) * 1998-09-21 2001-10-11 Univ Florida Agents antipaludeens
US7144904B2 (en) 1998-09-21 2006-12-05 University Of Florida Research Foundation, Inc. Iron binding agents
US7879886B2 (en) 1998-09-21 2011-02-01 University Of Florida Research Foundation, Inc. Iron binding agents
US6864270B2 (en) 1998-09-21 2005-03-08 University Of Florida Research Foundation, Inc. Iron binding agents
EP1488791A3 (fr) * 1998-09-21 2005-04-06 University Of Florida Research Foundation, Inc. Agents contre la malaria
WO2000029408A1 (fr) * 1998-11-13 2000-05-25 Smithkline Beecham P.L.C. Inhibiteurs de morpholino-ethoxybenzofuran protease
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7563784B2 (en) 2000-03-21 2009-07-21 Smithkline Beecham Corporation Protease inhibitors
US6635784B2 (en) 2000-09-29 2003-10-21 Eastman Chemical Company Process for the preparation of enantiomerically-enriched cyclopropylalanine derivates
WO2002088106A3 (fr) * 2000-11-17 2003-09-04 Medivir Ab Inhibiteurs de la cysteine protease
US7425562B2 (en) 2001-01-17 2008-09-16 Amura Therapeutics Ltd. Inhibitors of cruzipain and other cysteine proteases
US6958358B2 (en) 2001-01-17 2005-10-25 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
WO2002057248A3 (fr) * 2001-01-17 2002-10-03 Incenta Ltd Inhibiteurs de la cruzipain et autres cysteine proteases
US7132449B2 (en) 2001-01-17 2006-11-07 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US8921521B2 (en) 2003-06-18 2014-12-30 Ocera Therapeutics, Inc. Macrocyclic modulators of the Ghrelin receptor
US8334256B2 (en) * 2003-06-18 2012-12-18 Tranzyme Pharma Inc. Pharmaceutical salts of macrocyclic modulators of the ghrelin receptor
US9493505B2 (en) 2003-06-18 2016-11-15 Ocera Therapeutics, Inc. Macrocyclic modulators of the ghrelin receptor
US8604216B2 (en) 2003-09-09 2013-12-10 University Of Florida Research Foundation, Inc. Desferrithiocin derivatives and methods of use thereof
US8278458B2 (en) 2005-04-04 2012-10-02 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
US9994535B2 (en) 2005-04-04 2018-06-12 University Of Florida Foundation, Inc. Desferrithiocin polyether analogues
US9567309B2 (en) 2005-04-04 2017-02-14 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
US9096553B2 (en) 2005-04-04 2015-08-04 University Of Florida Research Foundation, Incorporated Desferrithiocin polyether analogues
US8722899B2 (en) 2005-04-04 2014-05-13 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
WO2007012180A1 (fr) * 2005-07-26 2007-02-01 Merck Frosst Canada Ltd. Inhibiteurs de la cystéine protéase de la famille de la papaïne pour le traitement des maladies parasitaires
US8324397B2 (en) 2007-03-15 2012-12-04 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
US9174948B2 (en) 2007-03-15 2015-11-03 University Of Florida Research Foundation, Inc. Desferrithiocin polyether analogues
US9730917B2 (en) 2007-03-15 2017-08-15 University Of Florida Research Foundation, Incorporated Desferrithiocin polyether analogues
US8642799B2 (en) 2007-11-29 2014-02-04 Merck Canada Inc. Cysteine protease inhibitors for the treatment of parasitic diseases
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine
US11931346B2 (en) 2011-12-16 2024-03-19 University Of Florida Research Foundation, Incorporated Uses of 4′-desferrithiocin analogs
WO2013127981A1 (fr) 2012-03-01 2013-09-06 Veterinärmedizinische Universität Wien Inhibiteurs de protéases pour le traitement des infections par trichomonas gallinae
EP2633855A1 (fr) 2012-03-01 2013-09-04 Veterinärmedizinische Universität Wien Inhibiteurs de la protéase pour le traitement d'infections par Trichomonas gallinae
US10010535B2 (en) 2013-11-22 2018-07-03 University Of Florida Research Foundation, Incorporated Desferrithiocin analogs and uses thereof
US10570104B2 (en) 2015-04-27 2020-02-25 University Of Florida Research Foundation, Incorporated Metabolically programmed metal chelators and uses thereof

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EP1068304A1 (fr) 2001-01-17
CO5080800A1 (es) 2001-09-25
NO20005032L (no) 2000-11-16
AR020065A1 (es) 2002-04-10
AU3482099A (en) 1999-11-01
NO20005032D0 (no) 2000-10-06
CN1304447A (zh) 2001-07-18
CA2327282A1 (fr) 1999-10-21
PE20000421A1 (es) 2000-05-21
TR200002940T2 (tr) 2001-02-21
JP2002511491A (ja) 2002-04-16
IL138628A0 (en) 2001-10-31
KR20010042535A (ko) 2001-05-25
PL343373A1 (en) 2001-08-13
DZ2752A1 (fr) 2003-09-15
MA26618A1 (fr) 2004-12-20
HUP0101513A2 (hu) 2001-08-28
EP1068304A4 (fr) 2001-05-09

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