EP0741696A1 - Malaria aspartic protease hemmende verbindungen - Google Patents

Malaria aspartic protease hemmende verbindungen

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Publication number
EP0741696A1
EP0741696A1 EP95907965A EP95907965A EP0741696A1 EP 0741696 A1 EP0741696 A1 EP 0741696A1 EP 95907965 A EP95907965 A EP 95907965A EP 95907965 A EP95907965 A EP 95907965A EP 0741696 A1 EP0741696 A1 EP 0741696A1
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Prior art keywords
radicals
amino
group
carbonyl
compound
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English (en)
French (fr)
Inventor
Mark A. Russell
Richard A. Mueller
Martin L. Bryant
Gunnar H. Hanson
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GD Searle LLC
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GD Searle LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D295/16—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
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • 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 malarial aspartic protease inhibitors and, more particularly, relates to novel compounds and a composition and method for inhibiting malarial aspartic proteases.
  • This invention in particular, relates to 2,5- diolpentylamine protease inhibitor compounds, a composition and method for inhibiting malarial aspartic proteases and for treatment or prophylaxis of a malarial infection.
  • the subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
  • Chloroquine has been a highly potent antimalarial, but a resistant organism pumps the drug out of the cell. Chloroquine' s mechanism of action is unknown, but very likely works by disrupting the metabolism of the acidic digestive vacuole in which it concentrates and in which hemoglobin degradation occurs. It is desirable to have new antimalarial compounds that also disrupt digestive vacuole function but cannot be pumped out of the organism.
  • the malaria parasite consumes hemoglobin as a main source of nutrients during the intraerythrocytic stage of infection.
  • Host cell cytoplasm is ingested by the cytostome, a specialized invagination at the parasite surface, from which vesicles pinch off to be transported to an acidic proteolytic compartment, the digestive vacuole.
  • hemoglobin is catabolized and the toxic heme moiety is sequestered in crystalline form as hemozoin.
  • Hemoglobin comprises ninety-five percent of the red blood cell's cytosolic protein.
  • the enzyme recognizes hemoglobin, making a single initial cleavage in the a chain between phe33 and leu34. This site is in the hinge region of hemoglobin that is involved in maintaining the integrity of the molecule as it binds oxygen. It is a highly conserved stretch of amino acids in all vertebrate hemoglobins. None of the hundreds of human variant hemoglobins that have been characterized have a homozygous defect in this region, consistent with the notion that the parasite has found a way to attack the hemoglobin molecule at a site that cannot be altered without deleterious consequences to the host.
  • t-butyl [ (S) -alpha- [[ (S) -1- [[ (IS,2S, 4S) -1- (cyclohexylmethyl) -2, 6-dihydroxy-4- isopropylhexyl] carbamoyl] -2-imidazol-4- ylethyl] carbamoyl]phenethyl] carbamate was prepared from (3S,5S, 6S) -6-amino-7-cyclohexyl-5-hydroxy-3- isopropyl-1-heptanol, t-butyl [ (S) -alpha- [[ (S) -1- [ [ (lS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4- isopropyl-6- (propionyloxy)hexyl] carbamoyl] -2-imidazol- 4-ylethyl] carbamoylJphenethyl] carba
  • the present invention is directed to malaria parasite inhibiting compounds and compositions.
  • the malaria parasite consumes hemoglobin as a main source of nutrients during the intraerythrocytic stage of infection.
  • This hemoglobin breakdown appears to be an ordered process requiring the specific action of an aspartic protease to initiate hemoglobin degradation. Inhibition of this enzyme would block the essential pathway of hemoglobin degradation, the main source of nutrients for the organism, and thereby lead to the death of the organism.
  • the present invention is directed to malarial aspartic protease inhibiting compounds and compositions, to a method of inhibiting malarial aspartic proteases, to processes for preparing the compounds and to intermediates useful in such processes.
  • the subject compounds are characterized as 2,5-diolpentylamine inhibitor compounds.
  • P 1 and P 2 are radicals each independently selected from the group consisting of hydrogen and alkanoyl radicals; or P 1 and P 2 taken together form a carbonyl CR 7 R S or a substituted carbon atom of formula ' wherein R 7 and R 8 are radicals each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals;
  • R ⁇ - , R2, R3 and R4 are radicals each independently selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl and aralkyl radicals;
  • R5 is a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, iso-butyl, tert- butyl, n-pentyl, iso-pentyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals;
  • R6 is a radical selected from the group consisting of hydrogen and alkyl radicals;
  • A is a radical selected from the group consisting of alkylcarbonyl, halo substituted alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl and a radical represented by the formula:
  • Y is selected from the group 0 and S
  • RIO is selected from the group consisting of hydrogen, -CH2S02NH2, -CO2CH3, -CH2CO2CH3, -C0 2 H, -CH 2 C0 2 H, - CH 2 CH 2 CONH , -CH 2 CONH 2 , -C0NH2, -CH2C(0)NHCH3, - CH2C(0)N(CH3)2, -CONHCH3, -CONH(CH3)2, -CH 2 SCH 3 , - CH 2 S(0)CH 3 , -CH 2 S(0) 2 CH 3 , -C (CH3 ) 2 (SCH3) , - C(CH3)2(S(0)CH3) , -C(CH3)2(S(0)2CH3) , alkyl, aminoalkyl, hydroxyalkyl, cyanoalkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkylalkyl, heteroary
  • R 11 is selected from the group consisting of hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocycloalkoxycarbonyl, heterocycloalkylalkanoyl, heterocycloalkylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkanoyl, heteroaroyl, alkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoaralkanoyl, aminocycloalkylalkanoyl, aminoalkanoyl, and mono- and disub
  • R 12 is selected from the group consisting of hydrogen, alkyl, aralkoxycarbonylalkyl, aminocarbonylalkyl, aminoalkyl, and mono- and disubstituted aminocarbonylalkyl and aminoalkyl radicals wherein said substituents are independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals; or R 11 and R 12 together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl radical.
  • a preferred class of malarial aspartic protease inhibitor compounds of the present invention are those represented by the formula: ( Formula II )
  • a more preferred class of malarial aspartic protease inhibitor compounds of the present invention are those represented by the formula:
  • the compounds of Formulas I, II and III can be in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts, prodrugs or esters thereof.
  • alkyl alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 10, preferably from 1 to about 8, carbon atoms.
  • examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
  • alkenyl alone or in combination, means a straight- chain or branched-chain hydrocarbon radial having one or more double bonds and-containing from 2 to about 18 carbon atoms preferably from 2 to about 8 carbon atoms.
  • suitable alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
  • alkynyl alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing from 2 to about 10 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl (propargyl) , butynyl and the like.
  • alkoxy alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • cycloalkyl alone or in combination, means an alkyl radical which contains from about 3 to about 10 carbon atoms and is a monocyclic or bridged cycloalkane or a benz-fused monocyclic cycloalkane which is optionally substituted by halo, nitro, cyano, alkoxy, aralkoxy, hydroxy, alkanoyl, alkanoylamino and the like, such as 1,2,3,4-tetrahydro-2-naphthoyl and 2-acetamido-l,2,3,4-tetrahydro-2-naphthoyl.
  • cycloalkylalkyl means an alkyl radical as defined above which is substituted by a cycloalkyl radical containing from about 3 to about 10, preferably from about 3 to about 8, and more preferably from about 3 to about 6, carbon atoms.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.
  • aryl alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, alkoxy, aralkoxy, halogen, hydroxy, amino, nitro, alkanoyl, alkanoylamino, aralkanoyl, aralkanoylamino and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4- (tert-butoxy)phenyl, 4-f-luorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like.
  • aralkyl alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.
  • aralkoxy carbonyl alone or in combination, means a radical of the formula aralkyl-O-C (0) - in which the term “aralkyl” has the meaning given above.
  • An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
  • aryloxy means a radical of the formula aryl-O- in which the term aryl has the meaning given above.
  • alkanoyl alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
  • cycloalkylcarbonyl means an acyl group derived from a cycloalkylcarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, 1, 2,3 , 4-tetrahydro-2-naphthoyl, 2- acetamido-1, 2,3, 4-tetrahydro-2-naphthoyl, and the like.
  • aralkanoyl means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl) , 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4- methoxyhydrocinnamoyl, and the like.
  • aroyl means an acyl radical derived from an aromatic carboxylic acid, which is optionally substituted by halo, nitro, cyano, alkoxy, aralkoxy, hydroxy, alkanoyl, aralkanoyl, alkanoylamino, aralkanoylamino and the like.
  • radicals examples include benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6- (benzyloxycarbonyl) -2- naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2- naphthoyl, 3- (benzyloxyformamido) -2-naphthoyl, and the like.
  • heterocycloalkyl alone or in combination, means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle which contains from about 3 to about 10 carbon atoms and heteroatoms, wherein from 1 to about 5 such atoms are heteroatoms and such heteroatoms are selected from the group consisting of nitrogen, oxygen and sulphur.
  • heteroaryl alone or in combination, means an aromatic monocyclic, bicyclic, or tricyclic heterocycle which contains from about 3 to about 10 carbon atoms and heteroatoms, wherein from 1 to about 5 such atoms are heteroatoms and such heteroatoms are selected from the group consisting of nitrogen, oxygen and sulphur.
  • Such heteroaryl radicals may optionally be substituted on one or more carbon atoms by radicals of halo, alkyl, alkoxy, hydroxy, and the like, and/or on a secondary nitrogen atom (i.e., -NH-) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl.
  • heterocycloalkyl and heteroaryl groups examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl, l-benzyloxycarbonylimidazol-4- yl, etc.), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2- quinolinyl, 3-quinolinyl, l-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquino
  • cycloalkylalkoxycarbonyl means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl has the significance given above.
  • aryloxyalkanoyl means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above.
  • heterocycloalkoxycarbonyl means an acyl group derived from heterocycloalkyl-O-COOH wherein heterocycloalkyl is as defined above.
  • heterocycloalkylalkanoyl is an acyl radical derived from a heterocycloalkyl-substituted alkylcarboxylie acid wherein heterocycloalkyl has the meaning given above.
  • heterocycloalkylalkoxycarbonyl means an acyl radical derived from a heterocyclyl-substituted alkane-O-COOH wherein heterocyclyl has the significance given above.
  • heteroaryloxycarbonyl means an acyl radical derived from a carboxylic acid represented by heteroaryl-O-COOH wherein heteroaryl has the meaning given above.
  • aminocarbonyl alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • aminoalkanoyl means an acyl group derived from an amino-substituted alkylcarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • halo or "halogen” means a halogen atom radical of fluorine, chlorine, bromine or iodine.
  • haloalkyl means an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen atom.
  • haloalkyl radicals examples include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1, 1, 1-trifluoroethyl and the like.
  • the term "leaving group” generally refers to groups readily displaceable by a nucleophiles such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N- hydroxybenzotriazole, halides, triflates, tosylates - OR and -SR and the like. Preferred leaving groups are indicated herein where appropriate.
  • R 1 and R 5 are as defined above and G 1 and G 2 independently are hydrogen and amino protecting groups, or alternatively, G 2 is R 6 .
  • Suitable amino protecting groups are well known in the art and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyl, benzyl, halo substituted benzyl and the like.
  • Preferred amino protecting groups are benzyl, t-butoxycarbonyl and carbobenzoxy.
  • the N- protected vinyl alcohol derivative can be prepared from the condensation of the corresponding vinyl anion, such as a Grignard or zinc reagent, and the corresponding N-protected amino acid aldehyde as illustrated in the following Grignard reaction scheme:
  • R 1 , R 5 , G 1 and G 2 are as defined above.
  • Acylation is preferably accomplished using acetic anhydride in pyridine.
  • the oxidation can be accomplished in methylene chloride at -78°C using ozone and a standard methyl thioether workup.
  • the ketone or aldehyde can be reacted with the ittig reagent of formula
  • R 2 is as defined above, under standard conditions in ether or tetrahydrofuran to produce the unsaturated ester of formula
  • the unsaturated ester can then be reduced under hydrogenation conditions, such as 5% Pt/C in methanol in the presence of 2 pounds per square inch of hydrogen (H ) , to produce the saturated ester of formula
  • R 1 , R 2 , R 5 , G 1 and G 2 are as defined above.
  • the saturated ester can then be converted into a lactone of the formula
  • R 1 , R 2 , R 5 , G 1 and G 2 are as defined above, in the presence of sodium methoxide in methanol.
  • the R 2 group can be introduced after the lactone formation.
  • the above ketone or aldehyde can be reacted with the Wittig reagent of formula
  • the alpha anion of the lactone can be formed through the addition of base, such as lithium diisoproylamide in tetrahydrofuran at -78°C, and reacted with R 2 X, wherein X is a leaving group such as halogen or sulfonate, to form the desired substituted lactone of formula
  • R 1 , R 2 , R 5 , G 1 and G 2 are as defined above.
  • the lactone can then be reacted with the nucleophile R 4 -, such as R Li or R 4 MgBr, in ether or tetrahydrofuran to produce the ketone of formula
  • the ketone can then be reduced under reducing conditions, such as sodium borohydride in methanol, to the corresponding alcohol of formula
  • R 1 , R 2 , R 4 , R 5 , G 1 and G 2 are as defined above.
  • the ketone can be further reacted with the nucleophile R 3 -, such as R 3 Li or R 3 MgBr, in ether or tetrahydrofuran to produce the alcohol of formula
  • R 1 , R 2 , R 3 , R 4 , R 5 , G 1 and G 2 are as defined above.
  • Deprotection of the amine can be accomplished using the standard conditions well known in the art and appropriate for the particular protecting group, such as hydrolysis with base, acid treatment of a t- butoxycarbonyl group or reductive hydrogenation.
  • the conditions selected must not affect the remaining portion of the molecule.
  • a carbobenzoxy group can be removed by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof, and a t-butoxycarbonyl group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride.
  • R 6 group on the amine if G 2 ⁇ R 6 and R 6 ⁇ H can be accomplished by reductive alkylation of the amino group with R 6 X, where R e X is an aldehyde or ketone.
  • R 6 X is an aldehyde or ketone
  • either the G 1 or G 2 group is removed followed by alkylation of the partially protected amine with R 6 X, where X is a halogen atom, or reductive alkylation with R 6 X, where R 6 X is an aldehyde or ketone, and then followed by removal of the remaining G 1 or G 2 group, to produce the amino alcohol of formula
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above,
  • the amine is then reacted with an alkylcarboxylic acid, acid halide or activated ester, halo substituted alkylcarboxylic acid, acid halide or activated ester, alkoxycarbonyl halide, bis (alkoxy)carbonyl, aralkoxycarbonyl halide, bis (aralkoxy) carbonyl, protected amino acid or corresponding derivative thereof represented by the formula
  • R 1 , R 2 , R 3 , R 4 , R 5 and R ⁇ are as de'fined above.
  • R 11 or R 12 is a hydrogen radical or a primary or secondary amine containing group
  • the nitrogen will have a protecting group.
  • Preferred N- protecting groups in this instance are a benzyloxycarbonyl group or a t-butoxycarbonyl group.
  • P 1 , P 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • P 1 and/or P 2 are/is alkanoyl
  • the addition can be accomplished by reaction of the corresponding alkylcarboxylic acid anhydride or acid halide with the alcohol groups, followed by removal of any N-protecting groups as disclosed above.
  • Selective alkanoylation and selective hydroylsis can be used to
  • SUBSTITUTE SHEET (RULE 2 ⁇ obtain mono-alkanoyl compounds (i.e., where one of P 1 or P 2 is a hydrogen radical) .
  • P 1 and P 2 taken together form a carbonyl the addition can be accomplished by reaction of the alcohol groups with phosgene or a phosgene equivalent, followed by removal of any N-protecting groups as disclosed above.
  • SIBSTTTUTE SHEET (RULE 26) 2 (S)-[ (1,1-Dimethylethoxy)carbonyl]amino-1-cyclohexyl- 5(R)-methylhexan-3 (S) ,6(RS)-diol
  • Example 8 as described in Example 6 to afford the title compound (80%) .
  • Nim-Tosyl-N-tBoc Histidine (1.6g, l. ⁇ el) was coupled to the amine from Example 8 (560mg, 2.44mmol) as described in Example 6 to afford the title compound
  • Example 10 The Boc protected amine from Example 10 (750mg, 1.21mmol) was converted into the title compound using the procedure described in Example 5 (320mg, 51%) . This compound was used without any further purification.
  • P. falciparum clone HB3 was grown at 37° C under 3% oxygen/3% carbon dioxide in RPMI medium using 5% human red blood cells (Trager and Jensen, Science 193:673-675, 1976, incorporated herein by reference) supplemented with 10% human plasma (Hui, et al., Trans. Roy. Soc. Trop. Med. Hyg. 625:625-626, 1984, incorporated herein by reference) . Synchronization was attained by treatment with sorbitol (Lambros and Vanderberg, J. Para ⁇ itol. 65:418-420, 1979, incorporated herein by reference) . Aspartic Protease Purification
  • Aspartic hemoglobinase was purified as previously described (Goldberg et al., J. Exp. Med. 173:961-969, 1991, incorporated herein by reference) with the following modifications. 1) Digestive vacuoles isolated by sorbitol lysis/differential centrifugation (Goldberg et al., Proc. Natl. Acad. Sci. USA 87:2931- 2935, 1990, incorporated herein by reference) omitting Percoll separation, were used as enzyme source. 2) Hydroxylapetite chromatography was performed by HPLC (Vander Jagt et al., Biochim. et Biophys.
  • the second aspartic protease was isolated as an earlier-migrating activity peak on the hydroxylapetite chromatography described above. A small amount of cysteine protease contamination was observed, which could be removed by repeating the DEAE chromatography.
  • reaction mixtures contained 150mM sodium acetate pH 5.0, 60,000 cpm (6.25 ⁇ M) 14 C-methylated globin (Dot avio-Martin and Ravel, Anal. Biochem. 87:562-565, 1978), lO ⁇ l vacuole extract or purified enzyme, and varying concentrations of inhibitor compound in a 40 ⁇ l final volume.
  • Late ring-stage cultures at 10% parasitemia were grown in the presence of various concentrations of inhibitor (diluted in RPMI medium) for 16 hours. At the end of this period, l ⁇ Ci (17.2Ci/mmol) of 3 H- hypoxanthine was added and the cultures were incubated for another 4 hours. Parasites were harvested and 3 H- hypoxanthine incorporation measured as previously described (Desjardins et al., Antimicrob. agents Chemother. 16:710-718, 1979, incorporated herein by reference) . As a control, the DMSO vehicle for the inhibitor was diluted in RPMI to the same extent and added to a similar culture. This had no effect on parasite hypoxanthine incorporation.
  • Late ring-stage cultures (10% parasitemia) were allowed to mature in the presence or absence of 10 ⁇ M inhibitor. At various time points, 24 ml aliquots of culture were harvested, brought to 1% Triton X-100, vortexed well, and centrifuged for 40,000 g-hours. The pellets were washed in water, then solubilized and heme content measured by the pyridine-hemochrome method (Slater and Cerami, Nature 355:167-169, 1992, incorporated herein by reference) .
  • Plasmodium falciparum strain FcBl is a chloroquine resistant strain originally obtained from Colombia. FcBl was cloned by limiting dilution. The clone used in the present study is denoted as FcBl(NC-
  • Parasites are grown in human erythrocytes.
  • Culture dishes, 100 mm contained 3% erythrocytes in RPMI1640 medium supplemented with 0.37mM hypoxanthine, 5mM glutamine, 35mM Hepes, 24mM sodim bicarbonate, 33mg/L gentamycin, and 10% horse serum (Gibco) , pH 7.2.
  • RPMI1640 medium supplemented with 0.37mM hypoxanthine, 5mM glutamine, 35mM Hepes, 24mM sodim bicarbonate, 33mg/L gentamycin, and 10% horse serum (Gibco) , pH 7.2.
  • Three days prior to the inhibitor study parasites were switched to medium that does not contain added hypoxanthine.
  • the inhibitors to be tested were dissolved in DMSO.
  • the stock solutions were kept at -20°C.
  • Working solutions were prepared by diluting the stock solutions with DMSO.
  • the inhibitor, in l ⁇ l DMSO, was added to microtiter wells containing 250 ⁇ l medium to give a constant final concentration of 0.4% DMSO.

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