MALARIAL ASPARTIC PROTEASE INHIBITORS

Abstract: 2,5-Diolpentylamine protease inhibitor compounds are effective as malarial aspartic protease inhibitors. Such compounds and compositions containing such compounds are effective for treatment or prophylaxis of malarial infections.

Description: MALARIAL ASPARTIC PROTEASE INHIBITORS BACKGROUND OF THE INVENTION 1. Field of the Invention 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. 2. Related Art Malaria afflicts several hundred million people world-wide, killing almost 2 million per year, mostly children. Vaccines have so far be ineffective in controling malaria. Prophylactic and therapeutic use of existing drugs have resulted in rampant drug resistance. Treatment of the most deadly malaria species, Plasmodium falciparum, is almost obsolete. Thus, there is a desperate need for new chemotherapeutic agents. 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. Here, hemoglobin is catabolized and the toxic heme moiety is sequestered in crystalline form as hemozoin. By the end of the trophozoite stage of the cycle, which lasts only a few hours, most of the host cell hemoglobin has been consumed. Hemoglobin comprises ninety-five percent of the red blood cell's cytosolic protein. It is likely that several enzymes participate in hemoglobin digestion. Indeed, over the past several years hemoglobinase activities have been ascribed to various members of the cyεteine and aspartic protease families (Vander Jagt et al., Biochem. Pharmacol. 36:3285-3291, 1987; Rosenthal et al., J. Clin. Invest. 82:1560-1566, 1988; Rosenthal and Nelson, Mol. Biochem. Parasitol. 51:143-152, 1992; Vander Jagt et al. , Biochem. et Biophys. Acta 1122:256-264, 1992; Goldberg, Infect. Agents and Dis. 1:207-211, 1992). Methods for isolating the digestive vacuoles has been developed that permits analysis of vacuolar enzymes with minimal contamination by extravacuolar proteases. Cleavage of native hemoglobin has been studied using digestive vacuole extracts in the presence of a variety of enzyme inhibitors to determine the classes of proteases involved in hemoglobin catabolism. The aspartic protease inhibitor pepstatin was found to block the initial events in hemoglobin digestion (Goldberg et al., Proc. Natl. Acad. Sci USA 87:2931-2935, 1990) . A vacuolar aspartic hemoglobinase has been purified to homogeneity and characterized (Goldberg et al., J. Exp. Med. 173:961-969, 1991) . 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. Cleavage by the hemoglobinase in this hinge region appears to unravel the substrate, after which the hemoglobinase can make secondary cleavages at Ieul05/leul06, as well as thrl07/leul08 (Goldberg et al., Proc. Natl. Acad. Sci USA 87:2931-2935, 1990) . Mimetic compounds are known to be useful as inhibitors of the proteolytic enzyme renin. US Patent No. 5,140,011 discloses 2, 5-diolpentylamine protease inhibitor compounds useful for renin inhibition. For example, 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] carbamate was prepared from (3S, 5S, 6S) -6-amino-7-cyclohexyl-5-hydroxy-3- isopropylheptyl propionate, t-butyl [ (S) -alpha- [[ (RS) - 1- [ [ (IS,2S, 4S) -6-benzyloxy-l- (cyclohexylmethyl) -2- hydroxy-4-isopropylhexyl] carbamoyl] -2-imidazol-4- ylethyl] carbamoyl]phenethyl] carbamate was prepared from (2S,3S, 5S) -2-amino-7- (benzyloxy) -l-cyclohexyl-5- isopropyl-3-heptanol, and t-butyl [ (S) -alpha- [ [1- [ [ (IS,2S,4S)-l-(cyclohexylmethyl) -2-hydroxy-4- isopropyl-6-phenoxyhexyl]carbamoyl] -2-imidazol-4- ylethyl]carbamoyl]phenethyl] carbamate was prepared from (2S,3S, 5S) -2-amino-l-cyclohexyl-5-isopropyl-7- phenoxy-3-heptanol, However, although renin proteases are classified as aspartic proteases, compounds which are effective renin inhibitors generally cannot be predicted to be effective malarial aspartic protease inhibitors and effective renin inhibitors used in malarial aspartic protease inhibition may have undesirable side effects due to the renin inhibition. BRIEF DESCRIPTION OF THE INVENTION 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. Thus, 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. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a malarial aspartic protease inhibiting compound of the formula: (Formula I) or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein 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: wherein 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, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkyl radicals; 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 disubstituted aminocarbonyl and mono-, di- and tri- substituted aminoalkanoyl, aminoaralkanoyl and aminocycloalkylalkanoyl radicals wherein the substituents are independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl and aralkoxycarbonyl radicals and in the case of N,N- disubstituted aminocarbonyl and aminoalkanoyl radicals, said substitutents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical; and 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 ) or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein A, P 1 , P 2 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 and R 12 are as defined above with respect to Formula I. A more preferred class of malarial aspartic protease inhibitor compounds of the present invention are those represented by the formula: (Formula III) or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein A, P 1 , P 2 , R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 and R 12 are as defined above with respect to Formula I. 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. As utilized herein, the term "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. The term "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. Examples of suitable alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like. The term "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. The term "alkoxy", alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term "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. The term "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. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. The term "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. The term "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. The term "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. The term "aryloxy" means a radical of the formula aryl-O- in which the term aryl has the meaning given above. The term "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. The term "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. The term "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. The term "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. Examples of such radicals 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. The term "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. Such heterocycloalkyl radicals may optionally be substituted on one or more carbon atoms by radicals of halo, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., -NH-) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e. = N-) by oxido and which is attached via a carbon atom. The term "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. Examples of such heterocycloalkyl and heteroaryl groups are 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.), tetrahydroquinolinyl (e.g., 1,2,3, 4-tetrahydro- 2-quinolyl, etc.), 1,2,3 , 4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-l-oxo-isoquinolinyl, etc.), quinoxalinyl, β-carbolinyl, 2-benzofurancarbonyl, 1- ,2-, 4- or 5-benzimidazolyl, and the like. The term "cycloalkylalkoxycarbonyl" means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl has the significance given above. The term "aryloxyalkanoyl" means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term "heterocycloalkoxycarbonyl" means an acyl group derived from heterocycloalkyl-O-COOH wherein heterocycloalkyl is as defined above. The term "heterocycloalkylalkanoyl" is an acyl radical derived from a heterocycloalkyl-substituted alkylcarboxylie acid wherein heterocycloalkyl has the meaning given above. The term "heterocycloalkylalkoxycarbonyl" means an acyl radical derived from a heterocyclyl-substituted alkane-O-COOH wherein heterocyclyl has the significance given above. The term "heteroaryloxycarbonyl" means an acyl radical derived from a carboxylic acid represented by heteroaryl-O-COOH wherein heteroaryl has the meaning given above. The term "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. The term "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. The term "halo" or "halogen" means a halogen atom radical of fluorine, chlorine, bromine or iodine. The term "haloalkyl" means an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen atom. Examples of such haloalkyl radicals 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. Procedures for preparing the compounds of Formula I are set forth below. It should be noted that the general procedure is shown as it relates to preparation of compounds having the specified stereochemistry, for example, wherein the stereochemistry about the OP 1 group is designated as R. However, such procedures are generally applicable to those compounds of opposite configuration, e.g., where the stereochemistry about the OP 1 group is S. Preparation of Compounds of Formula I The compounds of the present invention represented by Formula I above can be prepared utilizing the following general procedure, which is based on Hanson and Lindberg, J. Org. Chem. 50:5399, 1985, incorporated herein by reference. An N- protected vinyl alcohol derivative of an amino acid having the formula wherein 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: The vinyl alcohol can be acylated and oxidized to the corresponding aldehyde (R 5 = H) or ketone of formula wherein 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 wherein R 2 is as defined above, under standard conditions in ether or tetrahydrofuran to produce the unsaturated ester of formula wherein R 1 , R 2 , R 5 , G 1 and G 2 are as defined above . 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 wherein 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 wherein R 1 , R 2 , R 5 , G 1 and G 2 are as defined above, in the presence of sodium methoxide in methanol. Alternatively, 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 SUBSTITUTE SHEET (RULE 261 17 followed by lactonization to the lactone of formula wherein R 1 , R 5 , G 1 and G 2 are as defined above. 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 wherein 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 SUBSTITUTE SHEET (RULE ? β wherein R 1 , R 2 , R 4 , R 5 , G 1 and G 2 are as defined above. The ketone can then be reduced under reducing conditions, such as sodium borohydride in methanol, to the corresponding alcohol of formula wherein R 1 , R 2 , R 4 , R 5 , G 1 and G 2 are as defined above. Alternatively, 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 wherein 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. For example, 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. The introduction of the 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. Alternatively, 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 H wherein 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 wherein Y, R 10 , R 11 and R 12 are as defined above, to produce the antiviral compounds of the present invention having the formula wherein A, R 1 , R 2 , R 3 , R 4 , R 5 and R β are as de'fined above. In the event R 11 or R 12 is a hydrogen radical or a primary or secondary amine containing group, then the nitrogen will have a protecting group. Preferred N- protecting groups in this instance are a benzyloxycarbonyl group or a t-butoxycarbonyl group. The addition of P 1 and/or P 2 can then be accomplished to form the desired anti-malarial compounds of formula wherein A, P 1 , P 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above. When 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) . When 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. When P 1 and P 2 taken together form a substituted carbon atom ^C 7 8 of formula * , wherein R' and R H are radicals as defined above, the addition can be accomplished by reaction of the alcohol groups in the presence of a suitable base, such as sodium hydride, potassium hydride or lithium diisopropylamide, with XYCR 7 R 8 , wherein X and Y are leaving groups such as halogen radicals, followed by removal of any N-protecting groups as disclosed above. Contemplated equivalents of the general formulas set forth above for the anti-malarial compounds and derivatives as well as the intermediates or compounds otherwise corresponding thereto and having the same general properties such as tautomers thereof and compounds wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g., wherein R is a higher alkyl group than that indicated. In addition, where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position, e.g., halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure. The chemical reactions described above are generally disclosed in terms of their broadest SUBSTITUTE SHEET (RULE ? application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional alternative reactions, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure- in any way whatsoever. SltøSmUTESHEET(RULE2W Example 1 4-[l(S)-[(l,1-Dimethylethoxy)carbonyl]amino-2- cyclohexylethyl] -4 (S) -butyrolactone The above lactone (5.00g, 16.3mmol), prepared according to the method of Hanson and Lindberg (J. Org. Chem. 50:5399, 1985, incorporated herein by reference) in methanol (100ml) was hydrogenated over 5% Rh/C at 60 psi, 60°C for 12 hours. The reaction mixture was filtered through celite (to remove the catalyst) , evaporated and the residue recrystallized from diethyl ether/pentane to afford the title compound (3.90g) Anal for C 17 H 29 N0 4 , Calc: C;65.57, H;9.39, N;4.50 Found: C; 65.58, H;9.22, N;4.54. Example 2 4- [1 (S) - [ (1, 1-Dimethylethoxy) carbonyl] amino-2- cyclohexylethyl] -2 (R) -methyl-4 (S) -butyrolactone To stirred solution of the lactone from Example 1 (800mg, 2.57mmol) in THF (20ml) at -78°C, lithium diisopropylamide (4.1ml, 2.1eq, Aldrich) in hexane was added. The reaction mixture was stirred for 30 mins at this temperature and then quenched with methyl iodide (0.5ml excess) . The reaction mixture was allowed to attain room temperature, evaporated and the residue partitioned between diethyl ether and potassium hydrogen sulphate solution. The organic extracts were separated, dried (Na 2 S0 4 ) and evaporated to afford a clear oil, which was purified by chromatography on silica (eluant; diethyl ether; pentane; 50:50)- to afford the title compound (520mg, 62%) as a white solid. Anal for C lg H 1 N0 4 , Calc: C;66.43, H; 9.60, N; 4.30, Found: C; 65.15, H;9.61, N;4.26. Example 3 4(S)-[1(S)-[(1, 1-Dimethylethoxy) carbonyl]amino-2- cyclohexylethyl] -l-butyl-l-hydroxy-2 (R) -methyl- 1,2,3, 4-tetrahydrofuran To a stirred solution of the lactone from Example 2 (325mg, lmmol) in THF (20ml) at -78°C, n-butyl lithium (1.6ml, l.βeq, 1.6M solution) was added dropwise. The reaction mixture was stirred at -78°C for 2 hours and then quenched with acetic acid (0.15ml). The reaction mixture was evaporated and the residue partitioned between ethyl acetate and saturated potassium hydrogen sulphate solution. The organic extracts were separated, dried (Na_S0 4 ) and evaporated to afford an oily residue which was further purified by chromatography (silica, eluant 50% diethyl ether/hexane) to afford the title compound. Anal for C 22 H 41 N0 4 0.8 H 2 0, Calc: C;66.40 H; 10.79, N;3.52. Found C;6.37, H;10.42, N;3.54. Example 4 2 (S) - [ (1,1-Dimethylethoxy) carbonyl]amino-1-cyclohexyl- 5 (R) -methyldecan-3 (S) , 6 (RS) -diol To a stirred solution of the lactol from Example 3 (174mg, 0.45mmol) in methanol (5ml) sodium borohydride (lOOmg in 10ml of methanol) was added dropwise over 10 min. The reaction mixture was quenched with IN hydrochloric acid, evaporated the residue extracted into diethyl ether. The organic extracts were washed with aqueous solutions of potassium hydrogen sulphate followed by potassium hydrogen carbonate. The organic extracts were separated, dried (Na 2 S0 4 ) and evaporated to afford the title compound (170mg) as a white solid. Anal for C 22 H 43 N0 4 , Calc: C;68.53, I N;3.63. Found: C;68.26, H;11.29, N;3.59. Example 5 2 (S)-Amino-1-cyclohexyl-5 (R) -methyldecan-3 (S) ,6(RS) - diol To a stirred solution of Boc amine from Example 4 (145mg, 0.377mmol) in methylene chloride (1ml) and methanol (05ml) at 0°C, a prechilled solution of trifluoroacetic acid (3ml) was added. The reaction mixture was stirred at 0°C for 30 min, evaporated and partitioned between IN potassium hydroxide solution and ethyl acetate. The organic layer was separated, dried (Na 2 SO and evaporated to afford the title compound as a clear oil. This compound was fully characterized in the next reaction. Example 6 1,1-Dimethyl N-[IS(1R*) -[ [ [lR*-[ [ [1R*- (Cyclohexylmethyl)-2R*,5-dihydroxy-4S*- methylnonyl]amino]carbonyl]-3- methylbutyl]amino]carbonyl] -2-phenylethyl]carbamate To a stirred solution of BocPheLeuC0 2 H (212mg, l.βeq) in methylene chloride (2.5ml) at -10°C, N- methyl piperidine (80ml) followed by isobutylchloroformate (67mg, 1.4eq) was added. The reaction mixture was stirred at -10°C for 30 min and the amine (lOOmg, 0.35mmol) from Example 5 in methylene chloride (2.5ml) was added. The reaction mixture was allowed to attain room temperature, stirred for a further 16 hours and evaporated to afford a yellow solid residue. The residue was dissolved in a 1:4 mixture of methanol:IN potassium hydroxide (20ml) stirred for 15 mins. The resulting solution was evaporated (to remove the methanol) and the aqueous remainder was extracted with ethyl acetate. The organic extracts were separated, dried (Na 2 S0 4 ) and evaporated to afford the title compound as a white foam, which was further purified by precipitation from diethyl ether. Anal for C 37 H 63 N 3 0 6 1H2), Calc: C;66.93, H;9.87, N;6.33. Found: C; 66.87, H;9.52, N;6.23. Example 7 SIBSTTTUTE SHEET (RULE 26) 2 (S)-[ (1,1-Dimethylethoxy)carbonyl]amino-1-cyclohexyl- 5(R)-methylhexan-3 (S) ,6(RS)-diol To a stirred solution of the lactone from Example 2 (1.490g, 4.3mmol) in THF (30ml) at -78°C, DIBAL (15ml, IM solution in THF) was added. The reaction mixture was allowed to warm to 0°C and maintained there for a further 2 hours. The reaction mixture was quenched with acetic acid (5ml) , evaporated and the residue extracted into ethyl acetate. The organic extracts were washed with saturated potassium hydrogen carbonate solution, separated, dried (Na 2 S0 4 ) and evaporated to afford a white residue which was further purified by chromotography on silica (eluant, diethyl ether) to afford the title compound (950mg, 66%) . Compound fully characterized at the next step. Example 8 2 (S) -Amino-1-cyclohexyl-5 (R)-methylhexan-3 (S) ,6(RS)- diol The Boc protected amine from Example 7 was converted into the title compound (45%) using the procedure described in Example 5 AAnnaall ffoorr CC 1133 HH 2277 NN00 22 00..llHH 22 OO,, CCalc : C ; 67 . 55 , H; 11 . 86 , N;6.06. Found: C; 67.42, H;11.89, N;5.95 Example 9 1SCLR*) -[ [ [lR*-[ [ [1R*- (Cyclohexylmethyl)-2R*,5- dihydroxy-4S*-methylpentyl]amino]carbonyl]3- methylpropyl]amino]carbonyl] -2-phenylethyl-4- morpholinecarboxylate N-[2- (1-Morpholino)carboxy-3- phenyl]propionylleucine was coupled to the amine from Example 8 as described in Example 6 to afford the title compound (80%) . Anal for CHNO, Calc: C;65.64, H;8.85, N;6.96. Found: C-65.61, H;8.89, N;6.36 Example 10 1,1-Dimethylethyl N-[1S(1R*) -[ [ [1R*- (Cyclohexylmethyl) -2R*, 5-dihydroxy-4S*- methylpenty1]amino] carbonyl] -2- [1- [ (4- methylphenyl) sulfonyl] -lH-imidazol-4- yl] ethyl]carbamate BocHN Nim-Tosyl-N-tBoc Histidine (1.6g, l.δel) was coupled to the amine from Example 8 (560mg, 2.44mmol) as described in Example 6 to afford the title compound (820 mg, 54%) as a white amorphous solid. Anal for C 31 H 48 N 4 0 7 S 0.9H 2 O, Calc: C;58.45, H;7.88, N;8.80. Found: C;58.15, H;7.48, N; 8.63 Example 11 N-[1S(1R*) - (Cyclohexylmethyl)-2R*,5-dihydroxy-4S*- methylpent-1-yl] -2R*-amino-3-[1-[ (4- methylphenyl) sulfonyl]-lH-imidazol-4-yl]propionamide 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. suBsππrrE SHEET (RULE 26) Example 12 lSUR*)-[ [ [lR*-[ [ [lR*-(Cyclohexylmethyl) -2R*,5- dihydroxy- 4S*-methylpentyl]amino]carbonyl]-2- (lH-imidazol- 4-yl)ethyl]amino]carbonyl] -2-phenylethyl N-[2- (Dimethylamino)ethyl] -N-methylcarbamate Seco-piperidine phenyllactic acid (135mg, l.βeq) was coupled to the amine from Example 11 (150mg, 0.29 mmol) as described in Example 6 to afford the title compound (820mg, 54%) as a white amorphous solid. Anal for C 34 H 54 N g 0 6 0.9H 2 O, Calc: C;62.13, H;8.53, N;12.79. Found: C;62.18, H;8.54, N;12.23. Example 13 N-[1S(1R*) -[ [ [1R*- (Cyclohexylmethyl) -2R*, 5-dihydroxy- 4S*-methylpentyl]amino]carbonyl]-2- (lH-imidazol-4- yl)ethyl] -2 (IH) -indolecarboxamide To a stirred solution of the amine from Example 11 (130mg, 0.25mmol) in methylene chloride (5ml) and DMF (0.2ml) indole-2-carbonyl chloride (90mg, 0.5mmol) was added. The reaction mixture was worked up as described in Example 6 to afford an oily resdiue which was triturated from diethyl ether to afford the title compound (95mg) . Anal for C 28 H 3g N 5 0 4 1.8H 2 0, Calc: C;62.02, H;7.92, N;12.92. Found: C;61.92, H;8.00, N;12.56. Example 14 The following experimental procedures were used for determination of antimalarial actitivies of selected malarial aspartyl proteinase inhibitors: Culture of Plasmodium falciparum 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. Paraεitol. 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. Acta 1122:256-264, 1992, incorporated herein by reference) instead of syringe column. 3) The acid fractionation step was omitted. Contamination of purified enzyme was assessed with a panel of inhibitors of other classes of proteases (PMSF, o-phenanthroline, E-64) as described (Goldberg et al., Proc. Natl. Acad. Sci. USA 87:2931-2935, 1990) and no detectable contaminants were seen. Additionally, purified enzyme was completely inhibited by 10 μM pepstatin. 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. Enzyme Incubations Purified digestive vacuoles were prepared and extract was made as previously described. For the trichloroacetic acid (TCA) assay, reaction mixtures contained 150mM sodium acetate pH 5.0, 60,000 cpm (6.25 μM) 14 C-methylated globin (Dot avio-Martin and Ravel, Anal. Biochem. 87:562-565, 1978), lOμl vacuole extract or purified enzyme, and varying concentrations of inhibitor compound in a 40μl final volume. Reactions were stopped after 2 hours by addition of TCA, centrifuged and the supernates assayed for radioactive proteolytic fragments as previously described (Goldberg et al., J. Exp. Med. 173:961-969, 1991). Inhibitor Effects on P. falciparum Culture 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, lμCi (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. Parasitemia in the cultures paralleled hypoxanthine incorporation. For the time course, ring-stage culture was incubated with or without addition of 10μM inhibitor for 6-21 hours. At the designated times, aliquots of culture were removed and blood smears prepared using Giemsa stain (Fisher) . Hemozoin Ouantitation Late ring-stage cultures (10% parasitemia) were allowed to mature in the presence or absence of 10μM 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) . The results of the enzyme inhibition and culture inhibition assays are summarized in Table 1. Table 1 Compd. of Enzyme Culture Example No. Cone. (μM) % Inhibition % Inhibition 9 10 74 45 9 2 24 9 0.5 18 9 0.1 5 10 10 23 66 12 10 16 13 10 26 29 When degradation was quantitated using a 14 C- globin assay, purified aspartic hemoglobinase was inhibited by the compound of Example 6 with an IC 50 of 5-6 x 10 ~7 M. When this assay was repeated using the second vacuolar aspartic protease, activity was inhibited 2% at lμM of this compound and 22% at 10μM of this compound. Using extract of purified digestive vacuoles, the compound inhibited proteolysis with an IC 50 of 4 x 10 _7 M. More than 80% of total vacuolar digestion was inhibited at 10μM of this compound. When native hemoglobin was used as substrate, this compound also blocked the large majority of vacuolar proteolysis. Example 15 The following alternative experimental procedures were used for determination of antimalarial actitivies of selected malarial aspartyl proteinase inhibitors: Strain of Parasite 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- 1) . This cloned strain is inhibited by chloroquine, IC 50 = 270-290 nm. Experimental Procedure 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. Three days prior to the inhibitor study, parasites were switched to medium that does not contain added hypoxanthine. On the day of the start of a inhibitor study, cultures were set at 1.5% hematocrit, 1% parasitemia in media without added hypoxanthine. Aliquots, 250μl, were added in triplicate to microtiter wells. This was followed by the addition of sterile 3H- hypoxanthine, 0.3μCi/well containing total of 5μM 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 lμl DMSO, was added to microtiter wells containing 250μl medium to give a constant final concentration of 0.4% DMSO. Control wells received lμl DMSO. The 96-well plates were placed in a gas chamber, flushed with 5%C0 2 , 95% air for 2 minutes. The chamber was then kept at 37°C for 48-72 hours. The contents of the wells were collected on filters with a cell harvester, washed with water, and then the filter disks were counted in liquid scintillation solution containing triton X-100. The cloned strain was inhibited by the compound of Example 6, IC 50 = 2 μg/ml.

Claims: WHAT IS CLAIMED IS: 1. A compound represented by the formula: or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein 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 X ;CR 7 R 8 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; Rl, 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: wherein Y is selected from the group consisting of 0 and S; RIO is selected from the group consisting of hydrogen, -CH2S02NH2, -CO2CH3, -CH2CO2CH3, -C0 2 H, -CH 2 C0 2 H, - CH2CH2CONH2, -CH 2 C0NH 2 , -C0NH2, -CH2C(0)NHCH3, - CH2C(0)N(CH3)2, -CONHCH3, -C0NH(CH3)2, -CH 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, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkyl radicals; 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 disubstituted aminocarbonyl and mono-, di- and tri- substituted aminoalkanoyl, aminoaralkanoyl and aminocycloalkylalkanoyl radicals wherein the substituents are independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl and aralkoxycarbonyl radicals and in the case of N,N- disubstituted aminocarbonyl and aminoalkanoyl radicals, said substitutents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical; and 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. 2. The compound of Claim 1 represented by the formula: or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein A, P 1 , P 2 , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 and R 12 are as defined in Claim 1. 3. The compound of Claim 2 wherein the stereochemistry of the carbon atom bound to the OP 1 group is designated as R or S. 4. The compound of Claim 2 represented by the formula: or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein A, P 1 , P 2 , R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 and R 12 are as defined in Claim 1. 5. The compound of Claim 4 wherein the stereochemistry of the carbon atom bound to the OP 1 group is designated as R or S. 6. The compound of Claim 4 wherein R→ is a radical selected from the group consisting of methyl, ethyl, n-butyl, n-pentyl, iso-pentyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals. 7. The compound of Claim 1 selected from the group consisting of 2 (S) - [ (1, 1-Dimethylethoxy) carbonyl] amino-1-cyclohexyl- 5 (R) -methyldecan-3 (S) , 6 (RS) -diol; 2 (S) -Amino-l-cyclohexyl-5 (R) -methyldecan-3 (S) , 6 (RS) - diol; 1,1-Dimethyl N- [IS (1R*) - [ [ [lR*-[[ [1R*- (Cyclohexylmethyl) -2R*, 5-dihydroxy-4S*- methylnonyl]amino]carbonyl] -3- methylbutyl]amino]carbonyl] -2-phenylethyl]carbamate; 2 (S) - [ (1,1-Dimethylethoxy)carbonyl]amino-1-cyclohexyl- 5 (R) -methylhexan-3 (S) , 6 (RS) -diol; 2 (S) -Amino-l-cyclohexyl-5 (R) -methylhexan-3 (S) , 6 (RS) - diol; 1S(1R*)~[ [ [lR*-[ [[1R*- (Cyclohexylmethyl) -2R*, 5- dihydroxy-4S*-methylpentyl]amino]carbonyl]3- methylpropyl]amino]carbonyl] -2-phenylethyl-4- morpholinecarboxylate; 1,1-Dimethylethyl N- [IS (1R*) - [ [ [1R*- (Cyclohexylmethyl) -2R*, 5-dihydroxy-4S*- methylpentyl]amino] carbonyl] -2- [1- [ (4- methylphenyl) sulfonyl] -lH-imidazol-4- yl] ethyl] carbamate; N-[1S(1R*) - (Cyclohexylmethyl) -2R*,5-dihydroxy-4S*- methylpent-1-yl] -2R*-amino-3- [1- [ (4- methylphenyl)sulfonyl] -lH-imidazol-4-yl]propionamide; 1S(1R*)~[[ [lR*-[ [[lR*-(Cyclohexylmethyl)-2R*,5- dihydroxy-4S*-methy lpentyl] amino] carbonyl] -2- ( 1H- imidazol - 4 -yl ) ethyl] amino] carbonyl] -2 -phenylethyl N- [2 - (Dimethylamino) ethyl] -N-methylcarbamate ; and N-[IS(1R*) -[ [ [1R*-(Cyclohexylmethyl) -2R*,5-dihydroxy- 4S*-methylpentyl]amino]carbonyl]-2- (lH-imidazol-4- yl)ethyl] -2 (IH) -indolecarboxamide. 8. A pharmaceutical composition comprising a compound of Claim 1 and a-pharmaceutically acceptable carrier. 9. A pharmaceutical composition comprising a compound of Claim 2 and a pharmaceutically acceptable carrier. 10. A pharmaceutical composition comprising a compound of Claim 4 and a pharmaceutically acceptable carrier. 11. Method of inhibiting a malarial aspartic protease comprising administering a protease inhibiting amount of a composition of Claim 8. 12. Method of treating a malaria infection comprising administering an effective amount of a composition of Claim 8.

Inventors: BRYANT MARTIN L, HANSON GUNNAR H, MUELLER RICHARD A, RUSSELL MARK A, BRYANT, MARTIN, L., HANSON, GUNNAR, H., MUELLER, RICHARD, A., RUSSELL, MARK, A.
Applicants: BRYANT MARTIN L, HANSON GUNNAR H, MUELLER RICHARD A, RUSSELL MARK A, SEARLE & CO, BRYANT, MARTIN, L., G.D. SEARLE & CO., HANSON, GUNNAR, H., MUELLER, RICHARD, A., RUSSELL, MARK, A.
Application year: 1995
Main classification: C07C271
IPC codes: A61K31, A61K38, A61P33, A61P43, C07C215, C07C233, C07C271, C07C311, C07C317, C07C323, C07D233, C07D235, C07D295, C07D307, C07D403, C07K5