EP1274679A1 - Inhibiteurs bifonctionnels de proteases paludeennes et leurs applications - Google Patents

Inhibiteurs bifonctionnels de proteases paludeennes et leurs applications

Info

Publication number
EP1274679A1
EP1274679A1 EP01924983A EP01924983A EP1274679A1 EP 1274679 A1 EP1274679 A1 EP 1274679A1 EP 01924983 A EP01924983 A EP 01924983A EP 01924983 A EP01924983 A EP 01924983A EP 1274679 A1 EP1274679 A1 EP 1274679A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
aryl
heteroaryl
compounds
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Withdrawn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
EP01924983A
Other languages
German (de)
English (en)
Inventor
Jens W. Eckstein
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.)
Enanta Pharmaceuticals Inc
Original Assignee
Enanta Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enanta Pharmaceuticals Inc filed Critical Enanta Pharmaceuticals Inc
Publication of EP1274679A1 publication Critical patent/EP1274679A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/22—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 with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods, compounds, and pharmaceutical compositions for treating malaria.
  • the compositions comprise compounds that act as bifunctional protease inhibitors that inhibit parasitic aspartyl proteases and parasitic cysteine proteases of the papain family.
  • the compounds of the present invention are useful for treatmg diseases, particularly parasitic diseases, which are mediated by the activity of such proteases.
  • the present invention relates to treating malaria by inhibiting plasmepsin I and II, and falcipain.
  • Malaria is the fourth largest infectious disease in the world, behind diarrheal diseases, tuberculosis and measles. In humans, the disease is caused by four species of protozoal parasites in the genus Plasmodium. Plasmodium vivax and Plasmodium falciparum are the most common, while Plasmodium ovale and Plasmodium malariae occur less frequently. The majority of deaths ( ⁇ 3 million per year) are children under the age of five. Approximately 90% of the cases (300-500 million per year) are reported from tropical Africa, an area with very limited economic resources. Historically, the pharmaceutical industry has not invested significantly in developing therapeutics for diseases that occur primarily in this area (Gibbons 1992). Although there are ongoing efforts directed towards development of a malaria vaccine, no suitable vaccine has been produced as yet.
  • Infection of humans by Plasmodium occurs with a bite from an infected Anopheles mosquito, which injects the parasite in its sporozoite stage into the host.
  • the parasite migrates through the blood stream to the liver, where it passes through a hepatic trophozoite stage before developing into a merozoite.
  • Merozoites are released into the blood stream where they invade erythrocytes (red blood cells) and develop from a "ring stage" into a more metabolically active trophozoite.
  • the trophozoite divides asexually to become a schizont, which ruptures the host erythrocyte, releasing daughter merozoites that invade other erythrocytes and reinitiate the cycle.
  • falciparum parasite which causes the most severe form of malaria and is responsible for by far the greatest proportion of deaths, has a 48 hour life cycle within host erythrocytes that is responsible for all of the clinical manifestations of falciparum malaria.
  • hemoglobin within the host erythrocyte is degraded and utilized as a source of nutrition by the parasite. Hemoglobin degradation is mediated by the action of several malarial proteases including the aspartic proteases plasmepsin I and II and the cysteine protease falcipain.
  • the present invention provides a novel class of compounds and pharmaceutically acceptable derivatives thereof that are bifunctional inhibitors of aspartic and cysteine proteases.
  • the compounds are bifunctional inhibitors of aspartic and cysteine proteases found in Plasmodium, namely plasmepsins I and II and falcipain.
  • the compounds are characterized in that they incorporate features of plasmepsin inhibitors and features of falcipain inhibitors so that a single molecule exhibits inhibitory activity against both types of proteases.
  • the compounds can be used alone or in combination with other agents including antimalarials, antibiotics, and vaccines, for the prophylaxis and treatment of malaria.
  • the invention provides a class of compounds represented by formula (I):
  • X represents either CH 2 , NH, O, or S and Y represents either NH, O, or S; in which the conformation around the central double bond between carbon atoms numbered 3 and 4 can be either cis (E) or trans (Z) and the stereochemical conformations around the four chiral centers numbered 1, 2, 5, and 6 can be any combination of R and S;
  • R' represents but is not limited to a residue of the following list:
  • R" and R"' can each be independently selected from, but are not limited to, the following list: lower alkyl, lower alkoxy, lower alkylthio, mono- or di-lower alkyl amino, aralkyl, arylkoxy, arylkylthio, arylkylamino, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkylthio, cycloalkylalylamino, lower cycloalkyl, aryl, arylkyl, and heteroaryl.
  • R" and R"' can also represent the side chain (R group) of an amino acid residue remaining after formation of the linkage bonds, the side chain being optionally substituted with any of the groups in the previous list, i.e., lower alkyl, lower alkoxy, lower alkylthio, mono- or di-lower alkyl amino, aralkyl, arylkoxy, arylkylthio, arylkylamino, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkylthio, cycloalkylalylamino, lower cycloalkyl, aryl, arylkyl, and heteroaryl.
  • R" and R"' are connected by a bridging moiety having 1-10 atoms comprised of any stable combination of C, N, O, or S.
  • This chain may be optionally substituted by a functionality including, but not limited to, halo, hydroxy, amino, lower alkyl, lower alkoxy, lower alkylthio, mono- or di-lower alkyl amino, oxo, thiono, alkylimino, mono- or di-alkylmethylidene.
  • the bridging group may also be unsaturated so as to include residues of alkenes, imines, alkynes and allenes.
  • any part of the bridging moiety may comprise part of an optionally substituted aromatic, heteroaromatic, or cycloalkyl, or heterocycloalkyl ring.
  • Amino acids from which the residues containing R" and R'" can be derived include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, arginine, phenylalanine, homo-phenylalanine, tyrosine, tryptophane, and histidine;
  • R" represents but is not limited to a residue of the following list:
  • R" and R'" represent the side chain of an amino acid naturally found in proteins
  • R" and R'" can also represent the side chain of an amino acid not naturally found in proteins, including an optical isomer or a modified form of an amino acid found in proteins.
  • R" and R'" can be optionally substituted as indicated above.
  • the present invention provides a set of novel bifunctional protease inhibitors having stereochemical diversity that are useful for the treatment and/or prophylaxis of parasitic infection, particularly malaria.
  • the invention provides pharmaceutical compositions including novel bifunctional aspartic and cysteine protease inhibitors.
  • the pharmaceutical compositions can be used alone or in combination with other agents for the prophylaxis and treatment of malaria.
  • the inventive compositions comprise an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, such as a diluent or excipient.
  • the invention provides methods for prophylaxis and/or treatment of conditions associated with parasitic infection, in particular malaria, by administering an effective amount of a bifunctional inhibitor of parasite aspartic and cysteine proteases to a host or patient.
  • an effective amount of a compound of the present invention is administered to the host or patient.
  • a compound of the present invention and an effective amount of one or more other compounds useful in the treatment of malaria are administered to the host or patient.
  • pharmaceutically acceptable derivative denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
  • Pharmaceutically acceptable derivatives thus include among others pro-drugs.
  • a pro-drag is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species.
  • An example of a pro-drug is an ester that is cleaved in vivo to yield a compound of interest.
  • Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
  • the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment of and/or prevention of parasitic infections, particularly malaria.
  • stable as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • alkyl includes both straight, branched and cyclic alkyl groups.
  • An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like.
  • the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups.
  • alkyl and other aliphatic groups preferably contain 1-6, or 1-3, contiguous aliphatic carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, - CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH -cyclohexyl moieties and the like, which again, may bear one or more substituents.
  • -C 3 or Ci-C ⁇ alkyl moieties are employed.
  • the terms " -C 3 -alkyl” and “ -C 6 -alkyl” refer to saturated, substituted or unsubstituted, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, and one and six carbon atoms, respectively, by removal of a single hydrogen atom.
  • Examples of C ⁇ -C 3 -alkyl radicals include, but are not limited to, methyl, ethyl, propyl and isopropyl.
  • Examples -C 6 -alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.
  • C 2 -C 6 alkenyl moieties are employed.
  • the term "C 2 -C 6 -alkenyl” denotes a monovalent group derived from a hydrocarbon moiety containing from two to six carbon atoms and having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Additionally, the C 2 -C 6 alkenyl moieties, as used herein, may be substituted or unsubstituted.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • C 2 -C 6 alkynyl moieties are employed.
  • the term " -C 6 -alkynyl” as used herein refers to a monovalent group derived from a hydrocarbon containing from two to six carbon atoms and having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • the C 2 -C 6 alkenyl moieties, as used herein may be substituted or unsubstituted.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • -C 6 -alkoxy refers to a d -C 6 -alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Examples of C ⁇ -C 6 -alkoxy but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • alkylamino refers to a group having the structure -NHR' wherein R' is alkyl, as defined herein.
  • alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
  • - C 3 alkylamino groups are utilized in the present invention.
  • -C 3 - alkylamino refers to one or two d -C 3 -alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • Ci -C 3 -alkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
  • substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to: F, Cl, Br, I, OH, NO 2 , CN, C(O)-C 1 -C 6 -alkyl, C(O)-aryl, C(O)-heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH-d-C 6 -alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C 1 -C 6 -alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 - heteroaryl, OCONH 2 , OCONH-d-C 6 -alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)
  • amino acid refers to an organic acid containing both a basic amino group (NH 2 ) and an acidic carboxyl group (COOH).
  • Amino acids include both ⁇ -amino acids, in which the -NH 2 group is attached to the carbon atom adjacent to the -COOH group and also acids in which the -NH 2 and -COOH groups are separated by more than one intervening carbon atom. Amino acids frequently exist as dipolar ions in aqueous solution.
  • amino acid may refer to the unionized or ionized form.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heteroaryl compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • aryl and heteroaryl refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one, two or three of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: F, Cl, Br, I, OH, NO 2 , CN, C(O)-d-C 6 -alkyl, C(O)-aryl, C(O)-heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 - heteroaryl, CONH 2 , CONH-d-d-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-d- C 6 -alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH-d
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic or hetercyclic moieties, may optionally be substituted.
  • heteroaliphatic refers to aliphatic moieties which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched, or cyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to: F, Cl, Br, I, OH, NO 2 , CN, C(O)-C 1 -C 6 - alkyl, C(O)-aryl, C(O)-heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH-d-C 6 -alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-d-C 6 -alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- d-C 6 -alkyl, OCONH-aryl, OCONH-heteroaryl,
  • halo and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • heterocycloalkyl refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • a "substituted heterocycloalkyl” group refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to: F, Cl, Br, I, OH, NO 2 , CN, C(O)-C 1 -C 6 -alkyl, C(O)-aryl, C(O)-heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH- d-Ce-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-d-C 6 -alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 ,
  • “Hydroxy-protecting group” refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable.
  • the use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf., for example, T. H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 2 nd edition, John Wiley & Sons, New York (1991).
  • hydroxy-protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert- butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl benzoyl, and the like.
  • oxo denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i.e. a carbonyl group).
  • protected-hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • protogenic organic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treatmg, as “treating” is defined immediately above.
  • Cysteine and aspartic proteases appear to act cooperatively to degrade hemoglobin, and inhibitors of either class of protease have been shown to have antimalarial activity.
  • the ability of cysteine protease inhibitors to kill parasites in culture was well correlated with their effectiveness at inhibiting cysteine proteinase activity in trophozoite extracts (Rosenthal, P. J., W. S. Wollish, et al. J Clin Invest 88(5): 1467-72, 1991; Li, Chen et al., 1996; Rosenthal, Olson et al., 1996). In a mouse model of infection with P.
  • the combination of these inhibitors exhibited a synergistic effect in blocking parasite metabolism and development, and was much more effective for the treatment of murine malaria than higher concentrations of either compound alone.
  • N-Me-pipa-Leu-homoPhe-NSPh N-methyl piperazine urea-leucine-homophenylalanine-phenyl vinyl sulfone
  • Plasmpepsins are very similar to other known aspartyl proteases that are targets of drug discovery and development, i.e. HIV protease, renin and cathepsin D.
  • plasmepsin I shows high homology with cathepsin D, and inhibitors of cathepsin D have been found to be active against plasmepsin I as well (Ring, Sun et al. 1993; Carroll, Johnson et al. 1998; Carroll and Orlowski 1998; Haque, Skillman et al. 1999).
  • the most potent compounds reported were peptidic in nature and are very hydrophobic, i.e., their pharmacological profile is not very favorable.
  • the present invention encompasses the recognition that inhibition of both cysteine and aspartic proteases, specifically falcipain and plasmepsin(s) is a more effective strategy against malaria parasites than inhibition of either class alone.
  • the invention recognizes both that inhibitors of falcipain and plasmepsin(s) exert synergistic effects and also that by targeting two different essential parasitic enzymes, the likelihood of resistance development is reduced.
  • the invention encompasses the recognition that it is desirable to accomplish dual inhibition by administering a single compound rather than a combination of agents.
  • the compounds of the present invention therefore, incorporate features of cysteine and aspartic protease inhibitors within a single molecule to provide bifunctional inhibitors capable of inhibiting both of these classes of protease.
  • the compounds of the present invention incorporate features of inhibitors of falcipain and plasmepsin(s) to provide bifunctional inhibitors capable of inhibiting both falcipain and plasmepsin(s).
  • a bifunctional inhibitor provides significant advantages over a combination of two separate inhibitors in terms of drug development, allowing for a lower overall dose, decreased expense, and increased convenience for the patient.
  • the inventive bifunctional inhibitor shown above includes a vinyl sulfone moiety, characteristic of a class of potent inhibitors of falcipain (Rosenthal, et al., 1996) and also retains features characteristic of plasmepsin inhibitors.
  • the compound is also characterized in that the amide bond present in both of the class-specific inhibitors is replaced.
  • peptidic compounds are not desirable pharmaceuticals, particularly for oral administration, because the peptide bond is highly susceptible to cleavage. While not wishing to be bound by any theory, it is likely that removal of the peptide bond results in increased stability and oral bioavailability of the inventive protease inhibitors.
  • the invention provides compounds and pharmaceutical compositions for the prophylaxis and treatment of conditions associated with parasitic infection, particularly malaria.
  • the pharmaceutical compositions can be used in combination with other agents.
  • Compounds of this invention comprise those of Formula (I) set forth above in the Summary, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein.
  • R and R"" are 3-Cl-Ph-O-CH 2 - and - SO 2 Ph, respectively, where Ph indicates a phenyl group.
  • R" and R'" are side chains of phenylalanine and homophenylalanine, respectively.
  • R represents a halogen
  • phenyl ring may be substituted at any available position but bears at most a single R group.
  • R" is the side chain of a hydrophobic amino acid, e.g., phenylalanine, leucine, isoleucine, or valine.
  • R" is one of the following:
  • R represents an OH group, a CH 3 group, or a halogen, and wherein the phenyl ring may be substituted at any available position but bears at most a single R group.
  • R'" is the side chain of a hydrophobic amino acid, e.g., phenylalanine, leucme, isoleucine, or valine.
  • R" is one of the following:
  • R represents a halogen or an O-alkyl group, and wherein the phenyl ring may be substituted at any available position but bears at most a single R group.
  • R" is one of the following:
  • inventive compositions encompass any and all combinations of the specific sets of selections for R, R", R", and R"" mentioned above. It will be appreciated by one of ordinary skill in the art that numerous asymmetric centers may exist in the compounds of the present invention. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers. In a preferred embodiment, the inventive compounds are available in pure form.
  • the present invention provides pharmaceutically acceptable derivatives of the foregoing compounds, and methods of treating animals using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. While the compounds and methods of the present invention are chiefly directed towards inhibition of the malarial cysteine and aspartic proteases, plasmepsin and falcipain, it is noted that a variety of other proteases are important in the life cycle of Plasmodium. In addition a number of other parasites utilize cysteine and/or aspartic proteases.
  • Trypanosoma cruzi Trypanosoma brucei
  • Leishmania mexicana Leishmania major
  • Schistosoma mansoni Onchocerca volvulus
  • Brugia species a variety of other protozoa and helminths.
  • These proteases and their roles in the respective organisms are described in Berry, C, Proteases of Infectious Agents, Academic Press, 1999, which is herein incorporated by reference.
  • compounds of the present invention may also be useful in treatment of diseases caused by these parasites, which include sleeping sickness, Chagas disease, leishmaniasis, schistosomiasis, onchocerciasis, etc., many of which are major illnesses in the developing world.
  • the compounds of the present invention can be tested in a variety of assays to determine their potency as inhibitors of cysteine and aspartic proteases, specifically as inhibitors of plasmepsin(s) and falcipain.
  • the compounds can be tested using in vitro assays in trophozoite extracts or using recombinantly derived proteases.
  • Assays to assess the effects of inventive protease inhibitors on the degradation of hemoglobin by parasites can be performed as described in Rosenthal et al., 1996, the contents of which are herein incorporated by reference.
  • one such assay consists of incubating trophozoites in the presence of an inventive compound, followed by microscopic examination to detect the marked food vacuole abnormality that has been correlated with a block in hemoglobin degradation. Analysis of hemoglobin accumulation within trophozoites can also be assessed by SDS-PAGE electrophoresis. The effects of the inventive inhibitors on parasite growth and development can also be assessed by using a modified standard [ 3 H] hypoxanthine assay as described in Silva, et al., 1996.
  • inventive inhibitors can be tested using in vivo models of malaria, for example in mice infected with the murine malaria parasite, Plasmodium vinckei as described in Semenov, et al., 1998, the contents of which are herein incorporated by reference.
  • Appropriate control compounds for use in these assays include known inhibitors of cysteine and aspartic proteases, particularly inhibitors of plasmepsin(s) and falcipain, described in the references cited herein and well known in the art.
  • a preferred assay for testing the ability of the inventive compounds to inhibit plasmepsin is performed as described in Silva, et al., 1996, the contents of which are herein incorporated by reference. Briefly, plasmepsin I and II are cloned into the pET vector under the control of the T7 promoter. The proteins are expressed in E. coli, purified from inclusion bodies, refolded, and activated. Kinetic assays are performed using a fluorogenic substrate, DABCYL-QRMFLSFP-EDANS, which mimics the primary hemoglobin cleavage site common to both plasmepsins I and II.
  • a baculovirus expression system is used. Briefly the gene for preprofalcipain is cloned into a pBlueBac2 baculovirus transfer vector (Invitrogen) and cotransfected with wild type Autographa californica nuclear polyhedrosis virus into insect cells, e.g., High-5 cells. Recombinant viruses are plaque purified and used for high level expression in insect cells. Methods for identifying recombinant baculoviruses are well known in the art and will be described further in the Examples.
  • the bifunctional inhibitors display significant inhibitory activity towards both cysteine and aspartic proteases, in particular towards the malarial proteases, plasmepsin(s) and falcipain, it is to be understood that the inventive compounds need not inhibit these proteases to the same extent.
  • an inventive compound may display greater inhibitory activity against plasmepsin(s), while in other embodiments an inventive compound may display greater inhibitory activity against falcipain.
  • the invention includes those inventive compounds that may display inhibitory activity towards falcipain but substantially no inhibitory activity towards plasmepsin(s) or vice versa.
  • the inventive compounds display sub-micromolar activity in the enzymatic assays described above.
  • the present invention provides compounds useful for the treatment of parasitic diseases, in particular for the treatment of malaria.
  • compounds of the present invention, or pharmaceutical compositions are utilized to treat or prevent an infection or disorder as described above.
  • the compounds of the present invention can exist in free form for treatment, or, where appropriate, in salt form, as discussed in more detail below.
  • one or more of the inventive compounds can be formulated with a pharmaceutically acceptable carrier to provide a pharmaceutical composition.
  • Compounds to be utilized in the pharmaceutical compositions include compounds existing in free form or pharmaceutically acceptable derivatives thereof, as defined herein, such as pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative, which upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof, e.g., a prodrug.
  • inventive compounds in conjunction with known therapies to provide combination therapies for the treatment of infections and disorders.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail inJ Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • suitable esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tefrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drag release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation and ear drops are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain propellants known in the art such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, and in certain embodiments, includes an additional approved therapeutic agent for use as a combination therapy.
  • an additional approved therapeutic agent for use as a combination therapy can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration. Instructions for use of the compound(s) may also be included.
  • parasitic infections are treated or prevented in a patient such as a human or other mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention is meant a sufficient amount of the compound to treat a parasitic infection, in particular malaria, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more antiparasitic agents or vaccines.
  • combination it is not intended to imply that the agents must be administered at the same time or formulated for delivery together, although these methods of delivery are within the scope of the invention.
  • each agent will be administered at a dose and on a time schedule determined for that agent. Particular combinations can be selected to maximize synergy between the agents.
  • Preferred agents for administration in combination with the inventive compounds include antimalarial drugs such as chloroquine, mefloquine, quinine, quinidine, fansidar, and atovaquone.
  • Preferred agents also include the less widely used drugs primaquine, proguanil, maloprim, and tetracyclines.
  • drugs such as artemisinin (de Vries, et al., Drugs, 52, 818-836, 1996) and related compounds such as artelinic acid, tafenoquine, pyronaridine, fosmidomycin, desferroxamine, and azithromycin currently under study for malaria treatment and/or prophylaxis are preferred agents for use together with the compounds of the present invention.
  • drugs such as artemisinin (de Vries, et al., Drugs, 52, 818-836, 1996) and related compounds such as artelinic acid, tafenoquine, pyronaridine, fosmidomycin, desferroxamine, and azithromycin currently under study for malaria treatment and/or prophylaxis are preferred agents for use together with the compounds of the present invention.
  • one or more of the inventive compounds described herein may be administered with each other or with other
  • R" stands for -CH 2 Ph, and R" stands for -CH 2 CH 2 Ph, where Ph represents a phenyl group.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'un des aspects de cette invention a trait à une nouvelle classe de composés qui sont des inhibiteurs bifonctionnels de protéases aspartiques et de cystéine protéases, notamment de protéases paludéennes, falcipaïne et plasmepsines. En inhibant ces protéases, les composés perturbent une fonction nécessaire à la croissance et à la survie du parasite, en l'occurrence la détérioration de l'hémoglobine. Ces composés se révèlent des plus utiles dans le traitement d'infections parasitaires, notamment du paludisme. L'invention concerne également des compositions pharmaceutiques renfermant ces composés. Elle porte, de surcroît, sur des méthodes de traitement et/ou de prévention d'infections parasitaires, du paludisme notamment, consistant à administrer ces composés, seuls ou associés à d'autres agents antiparasitaires, à des vaccins, etc.
EP01924983A 2000-04-21 2001-04-12 Inhibiteurs bifonctionnels de proteases paludeennes et leurs applications Withdrawn EP1274679A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US19902300P 2000-04-21 2000-04-21
US199023P 2000-04-21
PCT/US2001/012000 WO2001083433A1 (fr) 2000-04-21 2001-04-12 Inhibiteurs bifonctionnels de proteases paludeennes et leurs applications

Publications (1)

Publication Number Publication Date
EP1274679A1 true EP1274679A1 (fr) 2003-01-15

Family

ID=22735884

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01924983A Withdrawn EP1274679A1 (fr) 2000-04-21 2001-04-12 Inhibiteurs bifonctionnels de proteases paludeennes et leurs applications

Country Status (3)

Country Link
EP (1) EP1274679A1 (fr)
AU (1) AU2001251587A1 (fr)
WO (1) WO2001083433A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002078714A1 (fr) * 2001-03-30 2002-10-10 Jomaa Pharmaka Gmbh Formulations gastro-resistantes de composes anti-infectieux, bloquant la voie metabolique de la 2-c-methylerythrose-4, ainsi que leurs sels et esters

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL112759A0 (en) * 1994-02-25 1995-05-26 Khepri Pharmaceuticals Inc Novel cysteine protease inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0183433A1 *

Also Published As

Publication number Publication date
WO2001083433A1 (fr) 2001-11-08
AU2001251587A1 (en) 2001-11-12

Similar Documents

Publication Publication Date Title
US11786497B2 (en) High penetration prodrug compositions of retinoids and retinoids-related compounds
KR100430207B1 (ko) 효소억제제
JP5934184B2 (ja) ヒストンデメチラーゼｌｓｄ１及び／又はｌｓｄ２の阻害剤としてのトラニルシプロミン誘導体
JP2807093B2 (ja) アミノ酸誘導体
JP2768554B2 (ja) 金属タンパク質加水分解酵素阻害剤であるヒドロキサム酸誘導体
KR20170123640A (ko) 면역조절제로서의 1,2,4-옥사다이아졸 및 티아다이아졸 화합물
NZ579802A (en) Compounds for improving the efficacy of other drugs
US6500802B1 (en) Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine protease inhibitors
US20020107266A1 (en) Compounds, compositions and methods for treatment of parasitic infections
EP4159211A1 (fr) Composé présentant une activité physiologique telle qu'une activité antivirale
CA2092414A1 (fr) Derives n-(2-alkyl-3-mercaptoglutaryl)-amino-diazacycloalcanone et leur utilisation comme inhibiteurs de la collagenase
JP2000508666A (ja) 成長ホルモン放出特性を有する化合物
US11135153B2 (en) High penetration composition and uses thereof
ES2300330T3 (es) Inhibidores de peptido desformilasa.
RU2475498C1 (ru) Новые производные гемина с антибактериальной и противовирусной активностью
EP1274679A1 (fr) Inhibiteurs bifonctionnels de proteases paludeennes et leurs applications
ES2243495T3 (es) Inhibidores de la deformilasa de peptidos.
CN114699419A (zh) PLpro蛋白抑制剂在治疗或预防新型冠状病毒感染的药物中的应用
ES2374664T3 (es) Inhibidores de péptido desformilasa.
EP1844775A1 (fr) Agent thérapeutique pour le traitement de l'herpès génital
EP3050871B1 (fr) Nouveau dérivé de bis-amide et son utilisation
KR19980703588A (ko) 선택된 용해성 히드록실 함유 인돌로카르바졸의 에스테르
AU2011291398A1 (en) Antifungal agents and uses thereof
KR100485479B1 (ko) 금속 단백질 분해효소 저해제
JP2024008547A (ja) 抗菌性ジペプチド化合物

Legal Events

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

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20021111

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20031007

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

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

18D Application deemed to be withdrawn

Effective date: 20040420