WO1992016501A1

WO1992016501A1 - Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease

Info

Publication number: WO1992016501A1
Application number: PCT/US1992/002290
Authority: WO
Inventors: Roger D. Tung; David D. Deininger
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 1991-03-20
Filing date: 1992-03-20
Publication date: 1992-10-01
Also published as: AU1677092A

Abstract

This invention relates to a novel class of glycolic compounds which contain a linear backbone having four contiguous oxygen-substituted methine carbons. The compounds of this invention inhibit the ability of aspartyl protease from HIV to catalyze the hydrolysis of peptides. These novel compounds can be used to reduce production of infectious virions from chronically infected cells and can inhibit the further infection of host cells. As such, they are useful as therapeutic agents to treat acquired immunodefiency syndrom (AIDS), as well as AIDS-related complex (ARC), AIDS-related dementia, and non-symptomatic HIV infection.

Description

TETRAHYDROXYALKANE DERIVATIVES AS INHIBITORS OF HIV ASPARTYL PROTEASE

Background of the Invention

HIV infection is known to manifest as a variety of diseases resulting from opportunistic infections

secondary to low levels of T4 lymphocytes. Furthermore, CD4+ macrophages and monocytes are known to act as a reservoir for the HIV virus and may be responsible for direct neural cytotoxicity (J. of NIH Res. 3:23-25

(1991)). Thus, agents which interrupt the life cycle of the HIV virus can be used to treat AIDS-related complex (ARC), AIDS related dementia, and non-symptomatic HIV infection.

A number of anti-viral compounds have been synthesized that are designed to target various stages in the replication cycle of HIV. These include compounds that block viral attachment to CD4-positive T lymphocytes (e.g., sT4 soluble CD4), inhibit reverse transcription (e.g., zidovudine; AZT), and inhibit integration of viral DNA into cellular DNA. These compounds, however, are directed primarily to early stages of viral replication and do not block the production of infectious virions in chronically infected cells.

Recently, the focus of anti-viral drug design has been directed to inhibition of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus encoded proteases which are essential for replication. Thus, compounds that can inhibit the action of these essential proteases can be useful as therapeutic agents for treating chronic HIV infection. Summary of the Invention

This invention relates to a novel class of glycolic compounds which are potent inhibitors of the HIV aspartyl protease, as well as to therapeutic methods for inhibiting protease activity in certain aspartyl protease viruses. The compounds comprise a linear backbone having four contiguous oxygen-substituted methine carbons. As

described herein, compounds of this invention inhibit the ability of aspartyl protease from HIV to catalyze the hydrolysis of peptides. These novel compounds can be used to reduce production of infectious virions from chronically infected cells and can inhibit the further infection of host cells. As such, they are useful as therapeutic agents to treat acquired immunodeficiency syndrome (AIDS), as well as AIDS-related complex (ARC), AIDS-related dementia, and non-symptomatic HIV infection.

Detailed Description of the Invention

This invention relates to a novel class of HIV aspartyl protease inhibitors which contain a linear backbone having four continguous oxygen-substituted methine carbon. These compounds are derivatives of n, n+1, n+2, n+3 - tetrahydroxyalkanes or n, n+1,

n+2, n+3 - tetrahydroxyalkenes, wherein the oxygens at positions n and n+3 are involved in ester or ether

linkages and the oxygens at positions n+1 and n+2 are free hydroxyls. Furthermore, positions n to n+3 are all occupied by methine carbons wherein each carbon atom is attached to two other carbons atoms and a single oxygen atom. As such, the compounds of this invention are represented by Formula I:

and pharmaceutically acceptable salts thereof,

wherein A is hydrogen, (C1-C4) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, phenyl, azide, hydroxyl, NH-L, O-L, CH₂-NH-L, CH₂-0-L,

Ar-substituted (C1-C4) -straight or branched alkyl,

Ar-substituted (C2-C4) -straight or branched alkenyl;

wherein L is Ar-carbonyl, Ar-oxycarbonyl or (C1-C2)-alkoxycarbonyl which may be substituted with an Ar group; wherein Ar is a benzofused heterocycle with 1-2 heteroatoms independently chosen from O, N or S;

morpholino, phenyl, 2-naphthyl, 9-fluorenyl, 1-benzotriazole or phenyl substituted with 1-3 substituents independently selected from the group consisting of cyano, hydroxyl, amino, dimethylamino, methoxy,

benzyloxy and halo;

wherein B is H, (C1-C5) -straight or branched alkyl, (C2-C4)-straight or branched alkenyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-furyl, 3-furyl, 2-thienyl,

3-thienyl or phenyl, or (C1-C2) -alkyl substituted with CONH₂, OH, OCH₃ or SCH₃ ;

wherein D is hydrogen or oxygen;

wherein E and E' are independently (C1-C2) -alkyl or C2-alkenyl;

wherein G and G' are independently (C1-C4) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, (C5-C6) -cycloalkyl, (C5-C6) -cycloalkenyl, 2-furyl,

3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, phenyl or phenyl substituted with a substituent selected from the group consisting of hydroxy, (C1-C4) -straight or branched alkoxy, benzyloxy, halo, amino, dimethylamino, aminomethyl and dimethylaminomethyl; and

wherein K is (C1-C8) -straight or branched alkane which may be substituted with one or two Ar groups,

(C2-C8) -straight or branched alkene which may be

substituted with one or two Ar groups or wherein

A, B and D are independently selected from the groups recited above.

The stereochemistry at positions 1 and 2, and at the methine of K, if present, may be either (R) or (S), where (S) is preferred. The stereochemistry at positions 3 may be (R) or (S). Preferably, the compounds will have a molecular weight from about 450 to about 1100 atomic mass units (a.m.u.) and most preferably below about 950 a.m.u.

In a preferred embodiment, the compounds of this invention are represented by Formula II:

and pharmaceutically acceptable salts thereof,

wherein B is H (C1-C5) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-furyl, 3-furyl, 2-thienyl,

3-thienyl or phenyl, or (C1-C2) -alkyl substituted with CONH₂, OH, OCH₃ or SCH₃ ; wherein J is NHC(O)M, wherein M is aryl (Ar as defined above), (C1-C4) -alkyl which may be substituted with Ar, (C2-C4) -alkenyl which may be substituted with Ar, or azide;

wherein Z is hydrogen, (C1-C4) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, phenyl, Ar-substituted (C1-C4) -straight or branched alkyl,

Ar-substituted (C2-C4) -straight or branched alkenyl, O-(C1-C5)-straight or branched alkyl or alkenyl,

O-(C5-C6)-cycloalkyl or cycloalkenyl or CH-B-J where B and J are defined above.

Examples of some preferred compounds are shown in Tables I and II.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,

propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl

chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long

chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

The compounds described in this application may be synthesized using known techniques. For example, the novel compounds can be synthesized by derivatization of a precursor containing a vicinal diol or protected vicinal diol moiety, as described in the Example Section. Alternatively, the glycols can be produced by oxidation of a precursor containing an alkene group using, for example, osmium tetraoxide either alone or catalytically with another oxidizing reagent such as 4-methyl morpholine-4-oxide (VanRheenen, V. et al., Tetrahedron Lett., 1973-1976 (1976); Evans, D.A. and S.W. Kaldor, J. Org. Chem., 55: 1698-1700 (1990)). This reaction may be carried out in the presence of various ligands to promote asymmetric reaction (Wai, J.S.M. et al., J. Am. Chem.

Soc, 111:1123 (1989)). Reduction of vicinal diketones or α-hydroxy ketones using, for instance, metal hydrides, metal borohydrides, boranes, alkylsilanes or certain other reducing agents will also yield glycols (Larock, R.c, Comprehensive Organic Transformations, 527-552 VCH Publishers, Inc., New York, NY (1989)). Opening of an epoxide group using, for instance, hydroxide ion or an alkoxide followed by dealkylation will also produce the diol moiety. Another important method for forming the diol nucleus described for the above compounds is the reductive coupling of two aldehyde units, which may be the same or different (pinacol reaction). This reaction may be carried out using various low-valent metals

including titanium (McMurry, J.E., Ace. Chem. Res.,

16:405-411 (1983)) and vanadium (Freudenberger, J.K. et al., J. Am. Chem. Soc, 111:8014-8016 (1989)) among others, and by various lanthanide iodides (e.g., Namy, J.L. et al., Tetrahedron Lett., 24:765-766 (1983);

Imamoto, T. et al., Tetrahedron Lett., 23:1353-1356

(1982)) as well as by electrolysis (Chem. Rev., 62:1968

(1962)). This is not intended to comprise a comprehensive list of all means by which the compounds claimed in this application may be synthesized and further methods will be evident to those skilled in the art.

The novel compounds of the present invention are excellent ligands for aspartyl proteases, particularly HIV-1 and HIV-2 proteases. These compounds are designed to target and inhibit late stage events in HIV replication, i.e., the processing of the viral polyproteins by HIV encoded proteases. The compounds inhibit the proteolytic processing of viral polyprotein precursors by inhibiting aspartyl protease. Since aspartyl protease is essential for production of mature virions, inhibition of this process can thereby block virus spreading by inhibiting the production of infectious virions, particularly from chronically infected mammalian cells. These compounds also inhibit the ability of the HIV-1 virus to infect immortalized human T cells over a period of days, as determined by an assay of reverse transcriptase activity, a specific marker of viral replication. As such, the novel protease inhibitors can be administered as a therapeutic agent for treating AIDS.

Table 3 summarizes the inhibition constants of the compounds listed in Table 1 against the isolated enzyme (K_i), as well as for prevention of viral spread in human T cells (IC₅₀). The inhibition constants of these compounds against HIV-1 protease can be obtained

essentially as described by: Pennington, M.W. et al. in "Peptide 1990" (Gimet, E. and D. Andrew, Eds., 1990

Escom; Leiden, Netherlands). The ability of the

compounds to prevent infection of human CD4+

T-lymphocytes (H9 cells) by HIV-1 virus, (HTLV-IIIb isolate), can be carried out according to: Meek, T.D. et al., Nature, 343:90-92 (1990), where the extent of infection was determined by reverse transcriptase

activity: Popvic, M. et al., Science, 224:497-500

(1984). Table 3

Compound Ki(nM) IC₅₀(mM)

1 4 2

2 410 ND 3 25,500 ND 4 13,400 ND 5 20 >40 6 17 ND 7 43 >40 8 90 >40 9 865 >40 10 30 ND 11 10 >40 12 6,500 ND 13 117 >40 14 141 >40 15 70 >40 16 25 0.16 17 30 >40 18 250 ND 19 1.5 0.08 20 1,030 ND 21 590 ND 22 370 ND 23 420 ND 24 0.5 0.02 25 140 ND Table 3 (continued)

Compound Ki(nM) IC₅₀(mM)

26 5,300 ND 27 1,100 ND 28 20 0.6 29 1.6 0.08 30 6.5 ND 31 28 ND 32 3 0.08 33 20 0.08 34 2,100 ND 35 200 ND 36 48 0.08 37 12 >40

In addition to administering the present compounds to an HIV-1 positive patient, other anti-viral agents which interfere with the replication cycle of HIV can be administered to the patient as a method of potentiating the therapeutic effect of these compounds by targeting other events in the viral life cycle. For instance, the co-administered anti-viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA. Some of these anti-HIV agents include, zidovudine (AZT), polysulfated polysaccharides, sT4

(soluble CD4) which blocks attachment or adsorption of the virus to host cells and other compounds which block binding of virus to CD4 receptors on CD4 bearing T-lymphocytes. Other retroviral reverse transcriptase inhibitors, such as derivatives of AZT, can also be co-administered with the compounds of this invention to provide therapeutic treatment for substantially reducing or eliminating viral infectivity and the symptoms associated therewith.

Additionally, non-nucleoside inhibitors of reverse transcriptase such as TIBO or Neurapine may be used to potentiate the effect of these compounds, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase. These compounds may also be co-administered with other inhibitors of the HIV aspartyl protease to increase the effect of the therapy against various viral mutants or members of other HIV quesi species.

The compounds of this invention can also be used as inhibitory agents for other viruses which depend on

similar aspartyl proteases for obligatory events in their life cycle. These viruses include HIV-2 and HTLV-I. For these purposes the compounds of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectible aqueous or oleagenous suspension.

This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending

medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides.

Fatty acids such as oleic acid and its glyceride derivatives find use in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or similar alcohol.

The compounds may be administered orally, in the form of capsules or tablets, for example, or as an aqueous suspension or solution. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The compounds of this invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa

butter, beeswax and polyethylene glycols.

The compounds of this invention may also be admini- stered topically, especially when the conditions

addressed for treatment involve areas or organs readily accessible by topical application.

For application topically to the skin, the compounds can be formulated in a suitable ointment containing the compound suspended or dissolved in, for example, a

mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil. sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.

Dosage levels on the order of 0.01 - 25 mg/kg per day of the active ingredient compound are useful in the treatment of the above conditions. The amount of active ingredient that may be combined with the carrier

materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors, including the activity of the

specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the severity of the infection.

The invention will be further illustrated by way of the following exemplification, which are not intended to be limiting in any way.

EXEMPLIFICATION

General

Thin layer chromatography (TLC) is carried out using 0.25 mm thick E. Merck silica gel

6OF₂₅₄ plates and elution with the indicated solvent system. Thick layer silica gel chromatography is also carried out using E.Merck 60 F₂₅₄ plates of 0.5, 1.0, or 2.0 mm. Detection of the compounds is carried out by treating the plate with a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or by exposure to UV light when appropriate. Thick layer silica gel chromatography is also carried out using E.Merck 60 F₂₅₄ plates of 0.5, 1.0, or 2.0 mm. Isolation of the compound is carried out by isolation of the band of silica containing the desired material, followed by elution with an appropriate solvent and concentration in vacuo.

TLC Solvent systems commonly used are as follow:

System A 95:5:0.5, CH₂CI₂/CH₃OH/NH₄OH

System B 90:10:1, CH₂CI₂/CH₃OH/NH₄OH

System C 5% diethyl ether/CH₂Cl₂

System D 8% CH₃OH/CH₂CI₂

System E 83.5/15/1.5 methylene chloride/diethyl ether/isopropanol

Analytical HPLC is carried out using a Water Delta Pak, 5 μM silica, C18 reversed-phase column, 3.9 mm ID × 15 cm L with a flow rate of 1.5 mL/min. Preparative HPLC is carried out using a Water Associates 15 μM silica, C18 reversed-phase RCM column, 25 mm ID × 10 cm L, with a flow rate of 8 mL/rnin.

Table A:

Mobile phase: A = 0.1% CF₃CO₂H in H₂O

B = 0.1% CF₃CO₂H in CH₃CN

Gradient: T = 0 min., A (95%), B (5%)

T = 20 min., A (0%), B (100%)

T = 22.5 min., A (0%), B (100%)

Table B:

Mobile phase: As table A

Gradient: T = 0 min., A (95%), B (5%) T = 15 min., A (0%), B (100%)

T = 16.5 min., A (0%), B (100%)

Table C:

Mobile phase: A= 0.1%H₃PO₄inH₂O

B= 0.1%H₃PO₄inCH₃CN

Gradient: T = 0 min., A (95%), B (5%)

T=15min.,A(0%),B(100%)

T = 16.5 min., A (0%), B (100%)

Table D:

Mobile phase: As table A

Gradient: T = 0 min.,A(40%),B(60%)

T=10 min.,A(0%),B(100%)

T = 12 min., A (0%), B (100%)

Table E:

Mobile phase: As table A

Gradient: T = 0 min., A (40%), B (60%)

T = 30 min., A (0%), B (100%)

T = 36 min., A (0%), B (100%)

Table F:

Mobile phase: As table A

Gradient: T = 0 min., A (50%), B (50%)

T = 30 min., A (0%), B (100%)

T = 36 min., A (0%), B (100%)

Table G:

Mobile phase: As table A

Gradient: T = 0 min., A (35%), B (65%)

T = 4min.,A(35%),B(65%)

T=15min.,A(0%),B(100%)

NMR spectral data is recorded using a Bruker AMX500, equipped with either a reverse or QNP probe, at 500 MHz, and is taken in deuterochloroform or dimethylsulfoxide as solvent. Tetramethylsilane was used as an internal standard except where noted.

Example 1 A. 4(S),5(S)-bis-((1'S)-1'-hydroxy-2'-phenylethyI)-2,2-dimethyl-1,3- dioxolane. To a -20 °C solution of 0.63 mL (3.4 mmol) of (-) dimethyl-2,3-O- isopropylidine-L-tartrate in 50 mL of tetrahydrofuran under an atmosphere of nitrogen was added, during 5 minutes, 5.16 mL (13.7 mmol) of a 2 molar solution of lithium

borohydride in tetrahydrofuran. After stirring an additional 5 minutes, the resulting solution was treated over 20 min with a 2 molar solution of benzylmagnesium chloride in tetrahydrofuran. The mixture was stirred for one hour at 0-2 °C, then to it was added 10 mL of water. After another 30 min, 5 g each of anhydrous magnesium sulfate and diatomaceous earth was added, and the rnixture was diluted with 200 mL of

dichoromethane and filtered, washing the filter pad with additional dichloromethane.

Concentration of the filtrate in vacuo yielded an oil which was purified by sequential low pressure silica gel column chromatography, using first 17.5% ethyl acetate in hexane, then a gradient of 0 to 2% tetrahydrofuran in dichloromethane to yield 336 mg of product. TLC: (System C) Rf = .24; (30% ethyl acetate/hexane) Rf = .52. NMR (CDCL₃): 7.19-7.33 (m, 10H), 3.72 (m, 2H), 3.77 (dd, 2H), 3.14 (dd, 2H), 2.5-3.15 (br s, 2H), 2.71 (dd, 2H), 1.46 (s, 6H)

B. 4(R),5(R)-bis-(1'(S)-((S)-N-carbobenzyloxyvalyIoxy)-2'- phenyIethyI))-2,2-dirnethyl-1,3-dioxolane. A solution of 28 mg (0.083 mmol) of the resultant compound of example 1 A in 2 mL of dichloromethane was treated

sequentially, at ambient temperature under an atmosphere of nitrogen, with 63 mg (0.25 mmol) of N-carbobenzyloxy-L-valine, 38 mg (0.20 mmol) of 1-(3-dimemylaminopropyl)- 3-ethylcarbodiimide hydrochloride, and 2 mg (0.01 mmol) of 4-pyrrolidinopyridine. The mixture was stirred for 3.5 days, then concentrated in vacuo. The residue was taken up in a mixture of ethyl acetate and water, and the organic layer was separated and washed sequentially with 5% KHSO₄ solution, saturated NaHCO₃ soution, and saturated NaCl solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using 2% diethyl ether in dichloromethane as eluent to yield 17 mg of product. TLC: (System C) Rf = 0.35. C. Compound 1. A solution of 8.7 mg (0.011 mmol) of the resultant compound of example 1B in 1 mL of methanol was treated, at ambient temperature, with 1.2 mL of 37% aqueous hydrochloric acid during 3 hr. Following this addition, the mixture was concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography, using 2% methanol andl0% diethyl ether in dichloromethane as eluant to yield 3.5 mg of white solid. HPLC (Table C): Rt = 15.3 min. NMR: 7.12-7.39 (m, 20H), 5.11 (s, 4H), 5.06 (d, 2H), 4.12 (ddd, 2H), 3.58 (ddd, 2H), 3.12 (dd, 2H), 1.90 (m, 4H), 2.31 and 1.96 (2 m, 2H), 1.28 (s, 2H), 0.79 (s, 6H), 0.67 (d, 6H).

Example 2 A. 4(R),5(R)-bis-(1'(S)-((S)-N-(9-nuorenylmethoxycarbon yl)-vaIyloxy)-2'-phenylethyl))-2,2-dimethyl-1,3-dioxolane. A solution of 42.4 mg (0.125 mmol) of the resultant compound of example 1A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 190 mg (0.56 mmol) of N-9-Flourenylmethoxycarbonyl-L-valine, 57.2 mg (0.3 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

hydrochlori de,. and catalytic 4-pyrrolidinopyridine. The mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHC03 solution, saturated NaCl then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a system C as eluent to yield 84.5 mg of product. TLC: Rf = 0.88 (5% diethyl ether /

dichloromethane).

B. Compound 2. A solution of 5.7 mg ( 0.006 mmol) of the resultant compound of example 2A in tetrahydrofuran was treated with a large excess of 15% HCl/tetrahydrofuran over 24 hours. Following this addition, the reaction mixture was concentrated in vacuo and the residue was purified by

preparative thick layer silica gel chromatography using 10% diethyl ether in dichloromethane to yield 1.3 mg of compound 2. TLC: Rf = 0.26, 10% diethyl ether in dichloromethane. HPLC (Table A) Rt=22.3 min. Example 3

A. (4R,5S)-4-((1'S)-1'-((S)-N-carbobenzyloxyvaIyloxy)-2'-phenylethyI)-5-(1"(S)-hydroxy-2"-phenylethyI)-2,2-dimethyl-1,3-dioxoIane. A solution of 26 mg (0.076 mmol) of the resultant compound of example 1A in 3 mL of

dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 23 mg (0.092 mmol) of N-carbobenzyloxy-L-valine, 21 mg (0.107 mmol) of 1-(3-dim ethylami nopropyl)-3-ethylcarbodiimide hydrochloride, and 1 mg (0.005 mmol) of 4-pyrroIidinopyridine. The rnixture was stirred for 3 days, then concentrated in vacuo to a small volume of several hundred microliters. This residue was purified by thick layer silica gel chromatography using system C chloride as eluant. Isolation of the major product band yielded 18 mg of product; TLC: (System C) Rf = 0.36. B . Compound 3. A solution of 6 mg (0.010 mmol) of the resultant compound of example 2A was dissolved in 0.4 mL of a solution of 15% concentrated HCl in THF and allowed to stand at ambient temperature for 6 h. The volatile components were removed in vacuo and the residue was redissolved in 0.4 mL of the above solution and allowed to stand at ambient temperature for 16 h. Volatile components were again removed in vacuo and the residue was purified by thick layer silica gel chromatography using System A as eluant. TLC: (System A) Rf = 0.30. HPLC: (Table A) Rt = 16.2 min.

Example 4

A. 4(R),5(R)-bis-(1'(S)-((S)-valyIoxy)-2'-phenylethyl))-2,2-dimethyI- 1,3-dioxoIane. A solution of 42.0 mg (0.05 mmol) of the resultant compound of example 1B in 3 mL of ethyl alcohol was added, at ambient temperature under a nitrogen atmosphere, to a slurry of 6 mg (14% by weight) of 10% palladium on carbon and hydrogenated for 4 h under a slight positive pressure of hydrogen. The mixture was filtered and concentrated in vacuo to yield 27.9 mg of product. NMR: (500 MHz., CDCI3) δ 7.12 - 7.28 (M, 10H), 5.23 (m, 4H), 3.98 - 4.03 (m, 4H), 2.92 - 3.13 ( m, 6H), 2.12 (m. 2H) 1.49 (s, 6H), and 0.75 -0.85 (m, 6H).

B. 4(R),5(R)-bis-((1'S)-1'-((S)-N-(3-isoquinoylcarbonyl)-vaIyloxy)-2'-phenylethyl)-2,2-dimethy 1-1,3-dioxoIane. A solution of 13.3 mg (0.025 mmol) of the resultant compound of example 4A. in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 12.7 mg (0.074 mmol) of 3-isoquinoline carboxylic acid hydrate, 0.015 mL (0.074 mmol) diisoproplyethylamine, 0.7 mg (0.05 mmol) of 1-hydroxybenzotriazole hydrate, and 11.7 mg (0.06 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred 60 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHCO3 solution, saturated NaCl then dried over MgSO4. filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a 5 - 10% gradient of (5/10/85 v/v/v NH4OH/methanol/dichloromethane) in dichloromethane as eluent to yield 14.4 mg of product. NMR: (500 MHz., CDC13) δ 9.22 (s. 2H), 8.60 (s, 4H). 8.08 (d, 2H). 7.99 (d,2H), 7.78 (t, 2H), 7.72 (t,2H), 7.08 -7.24 (m, 10H). 5.22 (bs, 2H), 4.83 ( dd. 2H), 4.01 (d, 2H), 2.96 -3.09 (m, 4H), 2.19 (m, 2H), 1.43 (s, 6H), 0.92 (d. 2H). and 0.78 (d. 6H).

C . Compound 4. A solution of 8.7 mg (0.01mmol) of the resultant compound of example 4B was deprotected as in example 2B except a slurry of NaH CO₃ in dichloromethane was added following completion of reaction and a filtration was carried out prior to concentration in vacuo. The residue was purified by preparative HPLC using (Table E) to yield 4.0 mg of product. TLC: Rf = 0.41 (30% diethyl ether / dichloromethane): HPLC (Table A): Rt = 20.3 min.

Example 5

A. 4(R),5(R)-bis-((1'S)-1'-((S)-N-(2-indolecarbonyl)-valyloxy)-2'-phenyIethyI)-2,2-dimethyl-1,3-dioxolane. A solution of 13.5 mg (0.025 mmol) of the resultant compound of example 2B in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 16.1 mg ( 0.01 mmol) of indole-2carboxylic acid, 0.02 mL (0.11 mmol)

diisoproplyethylamine, 6.7 mg (0.05 mmol) of 1-hydroxybenzotriazole hydrate, and 14.3 mg (0.075 mmol) 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 60 h and then the residue was taken up in ethyl acetate and washed with water, saturated NaHCO3 solution, saturated NaCl then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 2 -5% diethyl ether in dichloromethane as eluent to yield 12.8 mg of product. TLC: Rf = 0.15 (5% diethyl ether / dichloromethane).

C . Compound 5. A solution of 6.3 mg (0.008 mmol) of the resultant compound of example 5A was deprotected as in example 2B except a slurry of NaHCO₃ in dichloromethane was added following completion of reaction and a filtration was carried out prior to concentration in vacuo. The residue was purified by preparative HPLC using (Table A) to yield 3.7 mg of compound C. TLC: Rf = 0.16 (30% diethyl ether / dichloromethane): HPLC (Table A): Rt = 18.7 min. NMR (500 MHZ.. CDCL3) δ 7.78 (d, 2H). 3.37 (d. 2H). 7.06 - 7.29 (m, 16H). 6.91 (s, 2H), 6.24 (d, 2H), 5.19 ( m, 2H). 4.57 ( dd, 2H), 3.82 (d, 2H), 3.51 (bs, 2H), 3.13 (d. 2H), 2.81 (dd, 2H), 2.12 (m, 2H), 0.88 (d, 6H), and 0.70 (d, 6H).

Example 6

A. (4R,5R)-4-((1'S)-1'-((S)-N-carbobenzyIoxyvalyloxy)-2'-phenyIethyl)- 5-(1"(S)-((S)-(N^δ-tri phenylmethyl)-N^α-carbobenzyIoxyaspari ginyloxy)- 2"-phenylethyI)-2,2-dimethyl-1,3-dioxoIane. A solution of 43 mg (0.075 mmol) of the resultant compound of example 3A in 1.5 mL of methylene chloride was treated with 76 mg (0.15 mmol) of Cbz-N^δ-trityI-asparagine, followed by 29 mg (0.15 mmol) of 1-(3- dimethylammopropyl)-3-ethylcarbodiirnide hydrochloride, and 2.2 mg (0.015 rnmol) of 4- pyrrolidinopyridine. The mixture was stirred for 16 h, then diluted with diethyl ether and the resulting suspension washed sequentially with water, 10% potassium bisulfite solution, and brine. After drying over magnesium sulfate, the solution was concentrated and purified by thick layer silica gel chromatography using 25% ethyl acetate/hexane as eluant. Isolation of the major product band yielded 65 mg of product B . Compound 6. A solution of 8 mg (0.075 mmol) of the resultant compound of example 6A was dissolved in 0.4 mL 90% aqueous trifluoroacetic acid. After 10 min the residue was taken up in methylene chloride and again concentrated; this residue was again concentrated from a 1:1 mixture of methylene chloride and hexane to yield a white foam. Purication was achieved by preparative HPLC using table E to yield a white solid.

Residual triphenylmethanol was removed by dissolving the compound in diethyl ether, diluting with hexane, concentrating partially and filtering to yield 0.2 mg of white solid. TLC: (System B) Rf = 0.36. HPLC: (Table D) Rt = 9.3 min.

Example 7

A. (4R,5R)-4-((1'S)-1'-((S)-valyloxy)-2'-phenyIethyl)-5-(1" (S)-((S)-(N^δ-tri phenylmethyI)-aspari ginyIoxy)-2"-phenyIethyl)-2,2-dimethyI-1,3-dioxolane. A solution of 50 mg (0.047 mmol) of the resultant compound of example 6A in 4 mL of ethanol was treated with 10 mg of 10% palladium on carbon and hydrogenated for 16 h under a slight positive pressure of hydrogen. The mixture was filtered and the filtrated concentrated to yield 38 mg of a white foam which contained a slight ethanol solvation; TLC: (System B) Rf = 0.66. B. (4R,5R)-4.-(1'S)-1'-((S)-N-(2-Quinolylcarbonyl)-valyIoxy)-2'- phenylethyI)-5-(1"(S)-((S)-N^δ-trlphenylmethyl-N^α-(2-quinolylcarbonyl)-aspari ginyloxy)-2"-phenyIethyl)-2,2-dirnethyI-1,3-dioxoIane. A solution of 12 mg (0.015 mmol) of the resultant compound of example 7A in 1.5 mL of methylene chloride was treated with 7.8 mg (0.045 mmol) of 2-quinolinecarboxylic acid, followed by 8.6 mg (0.045 mmol) of 1-(3-dimethylammopropyl)-3-ethylcarbodiimide hydrochloride, and 6.1 mg (0.045 mmol) of 1-hydroxybenzotriazole hydrate. The mixture was stirred for 14 h and concentrated in vacuo to a small volume of several hundred microliters. This residue was purified by thick layer silica gel chromatography using 40% ethyl

acetate/hexane as eluant Isolation of the major product band yielded 14 mg of white solid. TLC: (50% ethyl acetate/hexane) Rf = .61.

C . Compound 7. A 11 mg (0.010 mmol) sample of the resultant compound of example 7B was deprotected as indicated in example 6B, except that the deprotection occurred during 30 min. A white solid was obtained which was purified by preparative HPLC using table E to yield 3.5 mg of compound 9; TLC: (System B) Rf = 0.58

Example 8

A. (4R,5S)-4-((1 'S)-1'-((S)-N-quinaldoyIvalyloxy)-2^,-phenylethyl)-5- (1"(S)-hydroxy-2"-phenyiethyl)-2,2-dimethyl-1,3.dioxolane. A solution of 16.3 mg (0.030 mmol) of the resultant compound of example 2B in

dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 21.0 mg ( 0.12 mmol) of quinaldic acid, 0.024 mL (0.14 mmol) diisoproplyethylamine, 8.0 mg (0.06 mmol) of 1-hydroxybenzotriazole hydrate, and 17.3 mg (0.075 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 48 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHCO₃ solution, saturated NaCl then dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 0-3% diethyl ether in dichloromethane as eluent to yield 14.4 mg of product. TLC: Rf = 0.39 (5% diethyl ether / dichloromethane). B. Compound 8. A solution of 10.7 mg (0.012 mmol) of the resultant compound of example 8A was dissolved in 0.2 mL of 90% aqueous

trifluoroacetic acid. After 1 h another 0.2 mL of 90% aqueous trifluoroacetic acid was added. After 2 h (total) the reaction mixture was concentrated in vacuo. The residue was purified by low pressure silica gel column

chromatography using a 8% diethyl ether in dichloromethane as eluent to yield 2.3 mg of product. TLC: Rf = 0.46 (30% diethyl ether / dichloromethane): HPLC (Table D) Rt=9.0 min. Example 9

A. 4(S),5(S)-bis-(1-oxo-2-phenylethyI)-2,2-dimethyl-1,3-dioxoIane. A solution of 1.28 mL (7.00 mmol) of (+) dimethyl-2,3-O-isopropylidine-D-tartrate and 11.7mL (83.9 mmol) of triethylamine in 100 mL of toluene was cooled in an ice bath and treated with 22.4 mL of a 1 M benzylmagnesium chloride/THF solution during 25 min. After 1.5 h, the mixture was quenched with saturated ammonium chloride and extracted with 10% potassium bisulfate, water, saturated sodium bicarbonate, and brine. Drying and concentration yielded an oily residue which was purified by silica gel chromatography, eluting with 6% ethyl acetate/hexane to yield 1.30 g of the product as a pale yellow oil. TLC: (30% ethyl acetate/hexane) Rf = 0.67.

B. 4(R),5(R)-bis-((1'S)-1'-hydroxy-2'-phenylethyI)-2,2-dimethyl-1,3-dioxolane. To a solution of 364 mg (1.10 mmol) of the resultant compound of example 9A in 5 mL of THF was added 1.6 mL of a 1 M solution of lithium aluminum hydride in THF. The mixture was stirred for 15 min., then treated with 0.3 mL of 2 N sodium hydroxide solution. The mixture was filtered, washing the filter cake with diethyl ether. The filtrate was concentrated to yield a colorless oil, which was purified by column chromatography using 22% ethyl acetate/hexane as eluant. TLC: (system C) Rf = .14 ; (30% ethyl acetate/hexane) Rf = .32. NMR (CDCL3): 7.18-7.33 (m, 10 H), 4.03 (s, 2H), 3.73 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.05 (d, 2H), 1.48 (s, 6H).

C. 4(R),5(R)-bis-((1'S)-1'-((S)-N-carbobenzyIoxyvalyloxy)-2'- phenyIethyI)-2,2-dimethyl-1,3-dioxoIane. A solution of 38 mg (0.11 mmol) of the resultant compound of example 9B in 3 mL of dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 45 mg (0.18 mmol) of N- carbobenzyloxy-L-valine, 34 mg (0.20 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 2 mg (0.01 mmol) of 4-pyrrolidinopyridine. The mixture was stirred for 10 h, then diluted with diethyl ether and washed with water, 5% potassium bisulfate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by thick layer silica gel chromatography using 7.5% diethyl ether/methylene chloride as eluant Isolation of the major product band yielded 31 mg of colorless oil.

D. Compound 9. A solution of 10 mg (0.012 mmol) of the resultant compound of example 9C was deprotected as indicated in example 6B, except that the deprotection occurred during 15 min. A coloriess oil was obtained which was purified by preparative HPLC using table F to yield 5.5 mg of compound 9; TLC (5% methanol/methylene chloride): Rf = 0.54, 0.60; these represent rotamers of the compound, which partially interconvert if the chromatogram is run subsequently in a second dimention. HPLC: (Table A) Rt = 18.8, 19.1 min. EXAMPLE 10

A. (4R,5S)-4-((1'S)-1'-((S)-N-(2-benzofuranoylcarbonyI)-valyloxy)-2'-phenyIethyl)-5-(1"(S)-hydroxy-2"-phenylethyI)-2,2-dlmethyI-1,3-dioxolane. A solution of 25.1 mg (0.046 mmol) of the resultant compound of example 2B in dichloromethane was treated sequentially, at ambient

temperature under an atmosphere of nitrogen, with 30.1 mg (1.86 mmol) of 2-benzofurancarboxylic acid, 0.03mL (1.86 mmol) diisoproplyethylamine, 19.0 mg (0.14 mmol) of 1-Hydroxybenzotriazole hydrate, and 27.0 mg (0.14 mmol) 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred 60 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, 5% KHSO₄, saturated NaHCO₃ solution, saturated NaCl then dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a 0 - 5% diethyl ether in dichloromethane as eluent to yield 35.4 mg of product. TLC: Rf = 0.53 (5% diethyl ether / dichloromethane). B. Compound 10. A sample of 13.8 mg (0.017 mmol) of the resultant compound of example 10A was dissolved in 0.3 mL of 90% aqueous

trifluoroacetic acid. After 1/2 h the mixture was concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 0 - 15% diethyl ether in dichloromethane as eluent to yield 5.3 mg of the title compound. TLC: Rf = 0.71 (25% diethyl ether / dichloromethane): HPLC (Table A) Rt=19.6 min. Example 11

A. 4(R),5(R)-bis-((1'S)-1'-((S)-N-quinoxoyIvalyloxy)-2'-phenyIethyl)- 2,2-dimethyI-1,3-dioxolane. A solution of 24.0 mg (0.044 mmol) of the resultant compound of example 2B in dichloromethane was treated

sequentially, at ambient temperature under an atmosphere of nitrogen, with 0.017 mL (0.13 mmol) diisoproplyethylamine and 20 mg (0.10 mmol)of 2- quinoxayl chloride. The mixture was stirred 1 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated NaHCO₃ solution, saturated NaCl then dried over MgS0₄, filtered and

concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a 0 - 5% diethyl ether in dichloromethane as eluent to yield 27.9 mg of product. NMR: (500 MHZ., CDCL3) δ 9.78 (s, 2H), 8.26 (d, 2H), 8.20 (m, 4H), 7.88 (m,4H). 7.19 (bd, 14H), 7.08 (q. 2H), 5.28 (bs, 2H), 4.75 (dd, 4H), 4.03 (d, 2H). 2.97 - 3.09 (m, 4H). 2.23 (m, 2H), 1.48 ( s, 6H), 0.97 (d, 3H), and 0.81 (d, 3H). B . Compound 11. A sample of 12.1 mg (0.0147 mmol) of the resultant compound of example 11A was dissolved in 0.3 mL of 90% aqueous

trifluoroacetic acid. After 1/2 h the mixture was concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 1% methanol in 10% diethyl ether in dichloromethane as eluent to yield 3.9 mg of product. TLC: Rf = 0.16 (30% diethyl ether / dichloromethane) HPLC (Table A) Rt=20.5 min.

Example 12

A. (4R,5R)-4-((1'S)-1'-((S)-N-(2-Pyri dyIacetyI)-vaIyIoxy)-2'- phenylethyl)-5-(1"(S)-((S)-N^δ-tri phenyImethyI-N^α-(2-pyri dylacetyl)-aspari ginyIoxy)-2"-phenylethyI)-2,2-dimethyl-1,3-dioxolane. A solution of 14 mg (0.018 mmol) of the resultant compound of example 7A in 2 mL of methylene chloride was treated with 9.4 mg (0.054 mmol) of 2-pyridylacetic acid hydrochloride, followed by 10 mg (0.045 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 7.3 mg (0.045 mmol) of 1-hydroxybenzotriazole hydrate and 10.4 μL (0.060 mmol) of diisopropylethylamine. The mixture was stirred for 16 h and concentrated in vacuo to a small volume of several hundred microliters. This residue was purified by thick layer silica gel chromatography using system A as eluant Isolation of the major product band yielded 13 mg of white solid. TLC: (System A) Rf = .37; (System B) Rf = .63.

B. Compound 12. A solution of 10 mg (0.012 mmol) of the resultant compound of example 12A was deprotected as indicated in example 6B, except that the deprotection occurred during 2 h. A yellow gum was obtained which was purified by thick layer silica gel chromatography using system B as eluant Isolation of the major product band yielded 13 mg of white solid. TLC: (System B) Rf = 0.35. HPLC: (Table B) Rt = 10.5 min.

Example 13 A. 4(R),5(R)-bis-(1'(S)-((S)-N^δ-tri phenylmethyl-N^α-benzyloxycarbonyl-aspari ginyIoxy)-2'-phenylethyl))-2,2-dimethyl-1,3-dioxolane. A solution of 202.2 mg (0.594 mmol) of the resultant compound of example 1A in

dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 906 mg (1.78 mmol) of Cbz-N^δ-trityl-asparagine, 340.2 mg (1.78 mmol) EDC , and catalytic 4-pyrrolidinopyridine. The mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHCO3 solution, saturated NaCl then dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a 3 - 6% diethyl ether in dichloromethane as eluent to yield 800 mg of product. TLC: Rf = 0.40 (5% diethyl ether / dichloromethane).

B. 4(R),5(R)-bis-(1'(S)-((S)-N^δ-tri phenylmethyI-aspari ginyloxy)-2'- phenyIethyI))-2,2-dimethyl-1,3-dioxoIane. A solution of 751 mg (0.567 mmol) of the resultant compound of example 13A in ethyl alcohol was added, at ambient temperature under a nitrogen atmosphere, to a slurry of 75 mg of 10% palladium on carbon and hydrogenated for 24 h under a slight positive pressure of hydrogen. After 24 hours the resulting slurry was dissolved in dichloromethane, then transfer to a Parr apparatus, recharged with catalyst, and hydrogenated at 20 psi for 24 h. The mixture was filtered and concentrated in vacuo. The residue was purified by filtration through a 1 inch pad of silica eluting first with 50% diethyl ether in dichloromethane and then with

(5/10/85 v/v/v NH4OH/melhanol/dichIoromethane) to yield 255 mg of product. TLC: Rf = 0.13 (25% diethyl ether / dichloromethane).

C. (4R,5R)-bis-((S)-N^δ-tri phenylmethyI-N^α-(2-quinoIylcarbonyl)- aspari ginyloxy)-2"-phenylethyl)-2,2-dimethyl-1,3-dioxolane. A solution of

24.9 mg (0.024 mmol) of the resultant compound of example 13B. in

dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 16.2 mg (0.094 mmol) of quinaldic acid, 0.018 mL (0.106 mmol) diisoproplyethylamine, 9.5 mg (0.071 mmol) of 1- hydroxybenzotriazole hydrate, and 13.5 mg (0.071 mmol) of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred 60 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHCO₃ solution, saturated NaCl then dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a 5 - 10% gradient diethyl ether in dichloromethane as eluent to yield 29.0 mg of compound 13C. NMR: (500 MHz., CDC13) δ 8.90 (d,2H), 7.55 - 8.24 (m,23H), 6.75

- 7.23 (m,31 H), 5.28 (bs,2H), 4.89 (q,2H), 4.03 (d,2H), 2.62 - 3.02 (m,8H), and 1.42 (S.6H).

D. Compound 13. A solution of 11.2 mg (0.008 mmol) of the resultant compound of example 13C was deprotected as in example 10B. The residue was purified by preparative HPLC using (Table E) to yield 4.2 mg of product; TLC: Rf

= 0.22 (30% diethyl ether / dichloromethane): HPLC (Table D): Rt = 13.7 min.

Example 14

A. (4R,5R)-4-((1'S)-1'-((S)-N.-2-IndoIylcarbonyl)-valyloxy)-2'-phenylethyI)-5-(1"(S)-((S)-N^δ-tri phenylmethyl-N^α-(2-indoIylcarbonyI). aspari ginyIoxy)-2"-phenylethyl)-2,2-dimethyl-1,3-dioxolane. A solution of 14 mg (0.018 mmol) of the resultant compound of example 7A in 2 mL of methylene chloride was treated with 8.5 mg (0.053 mmol) of 2-indole carboxylic acid acid, followed by 10 mg (0.053 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.1 mg (0.053mmol) of 1-hydroxybenzotriazole hydrate. The mixture was stirred for 16 h and concentrated in vacuo to a small volume of several hundred microliters. This residue was purified by thick layer silica gel chromatography using 2% methanol/rnethylene chloride as eluant Isolation of the major product band yielded 12 mg of white solid. TLC: (2% methanol/rnethylene chloride) Rf = .43.

B. Compound 14. A solution of 8 mg (0.0073 mmol) of the resultant compound of example 14A was deprotected as indicated in example 6B, except that the deprotection was carried out at 0° during 2.5 h. A yellow gum was obtained which was purified by thick layer silica gel chromatography using 5% methanol/rnethylene chloride as eluant Isolation of the major product band yielded 2.1 mg of white solid. TLC: (5% methanol/methylene chloride) Rf = 0.41. HPLC: (Table A) Rt = 16.5 min.

Example 15

A. (4R,5S)-4-((1 'S)-1 '-((S)-N-carbobenzyloxyisoleucyloxy)-2-phenylethyl)-5-(1 "(S)-(1"-hydroxy-2"-phenylethyl)-2,2-dimethy|-1,3- dioxolane. A solution of 345 mg (1.30 mmol) of carbobenzyloxy isoleucine in 10 mL of methylene chloride was cooled in and ice bath and treated with 128 mg (0.67 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 1 hour, then diluted with ether and washed rapidly with water and brine. After drying over magnesium sulfate, the solution was concentrated to yield a colorless oil, which was used directly for the next reaction.

A solution of 216 mg (0.63 mmol) of the resultant compound of example 1A in 6 mL of THF was cooled to -78° and treated with 252 μL (0.63 mmol) of n-butyllithium. The mixture was treated dropwise, during 1 min with a -78° solution of the above Cbz-isoleucyl anhydride in 62.5mL of THF). The mixture was stirred for 17 h, warming slowly to ambient temperature. Saturated ammonium chloride solution was added to quench the reaction, the mixture was partly evaporated to remove the bulk of the THF, and the residue was partitioned between methylene chloride and water. The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to yield a colorless oil which was purified by silica gel

chromatography using a gradient from 2% to 4% methanol in methylene chloride to yield 237 mg of colorless oil; TLC: (System C) Rf = 0.52. B. (4R,5R)-4-((1'S)-1'-((S)-N-carbobenzyIoxyisoleucyIoxy)-2'- phenylethyl)-5-(1 "(S)-((S)-N^δ-tri phenyImethyl-N^α- carbobenzyloxyaspari ginyIoxy)-2"-phenyIethyI)-2,2-dimethyl-1,3- dioxolane. A solution of 155 mg (0.263 mmol) of the resultant compound of example 15A in 7 mL of methylene chloride was treated with 267 mg (0.526 mmol) of Cbz-N^δ- trityl-asparagine, followed by 101 mg (0.526 mmol) of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and 4 mg (0.05 mmol) of 4-pyrrolidinopyridine. After stirring for 20 h, another several mg portion of 4-pyrrolidinopyridine was added, and stirring was continued for another day. The mixture was then diluted with diethyl ether and the resulting suspension washed sequentially with water, 10% potassium bisulfite solution, and brine. After drying over magnesium sulfate, the solution was concentrated the residue purified by silica gel chromatography using a gradient of 15% to 25% ethyl acetate/hexane to yield 182 mg of a colorless oil. TLC: (30% ethyl acetate/hexane) Rf = .48.

C. (4R,5R)-4-((1'S)-1'-((S)-isoleucyloxy)-2'-phenyIethyl).5-(1 "S)-(1"- ((S)-(N^δ-tri phenylmethyI)-aspariginyIoxy)-2"-phenylethyI)-2,2-dimethyl- 1,3-dioxoIane. A solution of 160 mg (0.148 mmol) of the resultant compound of example 15B in 6 mL of ethanol was treated with 25 mg of 10% palladium on carbon and hydrogenated for 18 h under a slight positive pressure of hydrogen. The mixture was filtered and the filtrated concentrated to yield 117 mg of a white foam. TLC: (System B) Rf = .74.

D. (4R,5R)-4-((1'S)-1'-((S)-N-(2-QuinoxalinelcarbonyI)-isoleucyIoxy)-2'-phenylethyI)-5-(1 "S)-(1 "-((S)-(N^δ-tri phenyImethyI)-N^α-(2- quinoxalinelcarbonyl)-aspari ginyloxy)-2"-phenylethyI)-2,2-dimethyl-1,3-dioxolane. A solution of 34 mg (0.042 mmol) of the resultant compound of example 15C and 22 μL (0.126 mmol) of diisopropylemylamine in 1.5 mL of methylene chloride was treated with 20 mg (0.105mmol) of 2-quinoxaloyl chloride. The mixture was stirred for 2 h, then diluted with diethyl ether and washed with water, saturated sodium

bicarbonate, and brine. After drying over magnesium sulfate and concentrating, the residue was purified by thick layer silica gel chromatography using 3% rnethanol/methylene chloride as eluant Isolation of the major product band yielded 40 mg of light yellow solid. TLC: (System A) Rf = .55.

E . Compound 15. A 38 mg (0.034 mmol) sample of the resultant compound of example 15D was deprotected as indicated in example 6B, except that the deprotection occurred during 1.5 h. A yellow foam was obtained which was purified by preparative HPLC using table E to yield 7.6 mg of compound 15; TLC: (7.5% iPrOH/methylene chloride) Rf = 0.56; HPLC: (Table C) Rt = 17.4 min.

Example 16 A . (2S ,3 R ,4 R,5S ) -3,4 -d i hyd roxy-2,5-b is -( S )-va lyloxy- 1 ,6-diphenylhexane. A solution of 96.0 mg (0.187 mmol) of the resultant compound of example 1C in tetrahydrofuran was added, at ambient

temperature under a nitrogen atmosphere, to a slurry of 0.11 mg (11% by weight) of 10% palladium on carbon and hydrogenated for 24 h under a slight positive pressure of hydrogen. The mixture was filtered and concentrated in vacuo to yield 51.3 mg of product. TLC: Rf = 0.25 (25% diethyl ether /

dichloromethane).

B. Compound 16. A solution of 8.2 mg (0.016 mmol) of the resultant compound of example 16A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 0.007 mL (0.041 mmol) diisoproplyethylamine and 5.7 mg (0.034 mmol) of 3-cyanobenzoyl chloride. The mixture was stirred 60 h and then concentrated in vacuo.

Following this addition, the reaction mixture was concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography using 10% diethyl ether in dichloromethane to yield 2.6 mg of product. TLC: Rf = 0.32 (30% diethyl ether / dichloromethane): HPLC (Table A) Rt=17.0 min.

Example 17

A. (3-(4S))-Cyclopentylacetyl-4-phenylmethyl-2-oxazolidinone. A solution of 2.01 g mg (16.0 mmol) of cyclopentylacetic acid in 8 mL of methylene chloride was cooled to 0° and treated with 2.79 mL (32.0 mmol) of oxalyl chloride, followed by 40 μL (0.5 mmol) of dirnethylformamide. The mixture was stirred for 40 min and concentrated in vacuo; the resulting yellow residue was taken up in methylene chloride and again evaporated. A 2.66 g (15.0 mmol) portion of (S)-4-phenylmethyl-2-oxazolidinone was dissolved in 40 mL of THF, cooled to -78° and treated with sufficient "butyllithium to form the yellow anion. This solution was treated with a -78° solution of the above

cyclopenrylaceryl chloride in 6 mL of THF in one portion. After stirring for 5 min in the cold, the mixture was treated with several mL of saturated ammonium chloride solution and stirred for 15 h, warming slowly to ambient temperature. The mixture was partially concentrated to remove volitile organics and the residue partitioned between a mixture of 3:1 (diethyl ether/methylene chloride) and half-saturated brine. The organic layer was separated and washed with saturated sodium bicarbonate, 10% potassium bisulfate, and brine, men dried over magnesium sulfate and concentrated to yield a yellow oil.

Purification on a silica gel column using 8%, then 10% acetone/hexane as eluant gave 3.26 g of white solid; TLC: (10% acetone/hexane) Rf = 0.25.

B. (3(2S),4S)-3-(2-Azido-2-cyclopentyIacetyl)-4-phenylmethyl-2- oxazolidinone. A solution of 2.87 g (10.0 mmol) of the resultant compound of example 17A was dissolved in 35 mL of THF and cooled to -78°. The solution was treated with 22 mL of a 0.5 M solution of potassium hexamethyldisilylamide, stirred for 10 min, and to the resulting solution was added a -78° solution of 3.87 g (12.5 mmol) of trisyl azide in 30 mL of THF. The reaction mixture was stirred for 1.5 min in the cold, then quenched with 2.62 mL (46.0 mmol) of acetic acid. This mixture was removed from the cold bath and allowed to warm to ambient temperature, then concentrated in vacuo. The residue was partitioned between a mixture of 3: 1 (diethyl ether/methylene chloride) and half-saturated brine. The organic layer was separated and washed with saturated sodium bicarbonate, then brine, then dried over magnesium sulfate and concentrated to yield a yellow oil. Purification on a silica gel column using a gradient of 35% to 45% methylene chloride/hexane as eluant gave 2.63 g of white solid; TLC: (3:1 methlene chloride/hexane) Rf = 0.69. NMR (CDCl₃): 7.21-7.38 (m, 5H), 5.0 (d, 1H), 4.7 (m, 1H), 4.23 (m, 2H), 3.34 (dd, 1H), 2.86 (dd, 1H), 2.47 (ddd, 1H), 1.88 (m, 1H), 1.52-1.80 (m, 6H), 1.80 (m, 1H).

C. 2-(S)-AzidocycIopentylacetic acid. A solution of 2.57 g (10.0 mmol) of the resultant compound of example 17B in 100 mL of THF and 35 mL of water to yield a two- phase solution. This rnixture was cooled to 0° and treated sequentially with 3.20 mL of aqueous 30% (wt) hydrogen peroxide and 657 mg (15.7 mmol) of lithium hydroxide monohydrate. After stirring for 30 min, the reaction was treated with a solution of 4.34 g (34.4 mmol) of sodium sulfite in 15 mL of water, followed by 4.0 g (48 mmol) of sodium bicarbonate. After an additional 5 min of stirring, the mixture was concentrated to remove volitile organics and the residue partitioned between water and methylene chloride. The aqueous phase extracted with more methlene chloride, rendered strongly acidic with 4N HC1 (pH ~1), and extracted with 4 portions of ethyl acetate. These organic layers were combined, dried over sodium sulfate, and concentrated to yield 1.26 g of colorless oil; TLC: (1:1 ethyl acetate/hexane with 0.25% acetic acid) Rf = 0.36. NMR (CDCI3): 3.73 (d, 1H), 2.39 (ddd, 1H), 1.77-1.90 (m, 2H), 1.64-1.75 (m, 2H), 1.56-1.64 (m, 2H), 1.39-1.52 (m, 2H).

D. (4R,5R)-4-((1'S)-1'-((S)-Azidocyclopentylacetoxy)-2'-phenylethyI)-5- (1"(S)-hydroxy-2"-phenylethyI)-2,2-dimethyl-1,3-dioxolane. A solution of

213 mg (1.26 mmol) of the resultant compound of example 17C in 4 mL of methylene chloride was cooled to 0° and treated with 220 μL (2.52 mmol) of oxalyl chloride followed by 8 μL of dimethylformamide. The rnixture was removed from the ice bathe and stirred for 40 min, then concentrated. The residue was taken up in methylene chloride and again concentrated, and the resulting residue was dissolved in 15 mL of benzene. This solution was treated with 450 mg (2.52 mmol) of silver cyanide, followed by 288 mg (0.841 mmol) of the resultant compound of example 1 A. The mixture was heated under reflux for 20 min, then cooled to 0° and treated with 240 μL (1.39 mmol) of diisopropylethylamine followed by 15 mg (0.1 mmol) of 4-dirnethylaminopyridine and 2 mL of methylene chloride. After stirring for 25 min, the mixture was diluted with methylene chloride and filtered, and the filtrate diluted with diethyl ether and washed with water, 10% potassium bisulfate, and brine. After drying over magnesium sulfate and concentrating, the residue was purified by silica gel chromatography using a gradient of 30% methylen

chloride/hexane to 100% methylen chloride. The title compound comprised 222 mg of colorless oil; TLC: (3:1 methlene chloride/hexane) Rf = 0.20. NMR (CDCI₃): 7.28-7.36 (m, 10H), 5.42 (m, 1H), 4.22 (dd, 1H), 3.87 (m, 2H), 3.46 (d, 1H), 3.12 (d, 1H), 3.11 (d, 1H), 3.02 (dd, 1H), 2.72 (m, 1H), 2.12 (ddd, 1H), 2.01 (br s, 1H), 1.71 (m, 1H), 1.39-1.55 (m, 4H), 1.51 (s, 3H), 1.46 (s, 3H), 1.24-1.39 (m, 2H), 1.16 (m, 1H).

Also isolated was 222 mg of 4(R),5(R)-bis-((1'S)-1'-((S)-Azidocyclopentylacetoxy)-2'-phenylethyl)-5-(1"(S)-hydroxy-2"-phenylethyl)-2,2-dimethyl-1,3-ciioxolane as a colorless oil; TLC: (3:1 methlene chloride/hexane) Rf = 0.58. NMR (CDCl3): 7.18-7.30 (m, 10H), 5.33 (m, 2H), 4.07 (d, 2H), 3.53 (d, 2H), 3.09 (dd, 2H), 3.00 (dd, 2H), 2.08 (ddd, 2H). 1.67 (m, 2H), 1.38-1.62 (m, 12H), 1.33-1.47 (m, 4H), 1.16 (m, 2H).

E. (4R,5R)-4-((1'S)-1'-((S)-Azidocyclopentylacetoxy)-2'-phenylethyl)-5-(1'S)-1 '-((S)-N-Carbobenzyloxyvalyloxy)-2^,-phenylethyl)-2,2-dimethyI- 1,3-dioxolane. A solution of 109 mg (0.221 mmol) of the resultant title compound of example 17D in 3 mL of methylene chloride was treated with 111 mg (0.442 mmol) of N-Carbobenyloxy-valine, 93 mg (0.486 mmol) of 1-(3-dimethylaminopropyl )-3- ethylcarbodiimide hydrochloride, and 8 mg (0.05 mmol) of 4-dimerthylaminopyridine. After stirring for 18 h, the mixture was diluted with diethyl ether and the resulting suspension washed sequentially with water, saturated sodium bicarbonate solution, and brine. After drying over magnesium sulfate, the solution was concentrated the residue purified by silica gel chromatography using 10% acetone/hexane to yield 125 mg of a colorless oil; TLC: (10% acetone/hexane) Rf = 0.23.

F. (4R,5R)-4-((1'S).1'-((S)-AminocycIopentylacetoxy)-2'-phenylethyI)-5- (1'S)-1'-((S)-valyIoxy)-2'-phenyIethyl)-2,2-dimethyI-1,3-dioxolane. A solution of 110 mg (0.15 mmol) of the resultant title compound of example 17E in 3 mL of THF was added to a suspension of 30 mg of 10% palladium on carbon in 5 mL of THF. The mixture was stirred for 24 h under a slight positive pressure of hydrogen, tiien filtered and concentrated to 85 mg colorless oil. TLC: (System B) Rf = 0.60.

G. (4R,5R)-4-((1'S)-1'-((S)-N-(2-Benzofuranoyl)-vaIyIoxy)-2'- phenyIethyl)-5-(1"(S)-((S)-N(2-benzofuranoyI)-aminocycIopentyIacetoxy)- 2"-phenyIethyI)-2,2-dimethyl-1,3-dioxolane. A solution of 16 mg (0.029 mmol) of the resultant compound of example 17F along with 14 mg (0.088 mmol) of benzofuran, 17 mg (0.088 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 12 mg (0.088 mmol) of 1-hydroxybenzotriazole hydrate in 3 mL of mediylene chloride was stirred for 16 h. The solution was diluted with diethyl ether and extractedc with water, saturated sodium bicarbonate, and brine, then dried over magnesium sulfate and concntrated to a yellow oil. This residue wa purified on a silic gel column, eluting with a gradient of 0% to 3% methanol/methylene chloride to yield 24 mg of white foamy solid. TLC: (System A) Rf = 0.83.

H . Compound 17. A 20 mg (0.023 mmol) sample of the resultant compound of example 17G was deprotected as indicated in example 6B, except that the deprotection occurred during 40 min. A white foam was obtained which was purified by thick layer silica gel chromatography using system E as eluant. Isolation of the major product band yielded 11 mg of white solid. TLC: (system E) Rf = 0.43. HPLC: (Table A) Rt = 19.8 min.

Example 18 A. Compound 18. A solution of 7.1 mg (0.014 mmol) of the resultant compound of example 16A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 5.4 mg (0.032 mmol) of piperonylic acid, 0.006 mL (0.035 mmol) diisoproplyemylamine, 4.0 mg (0.03 mmol) of 1-hydroxybenzotriazole hydrate, 5.7 mg (0.03 mmol) 1-(3-dimethylamιinopropyl)-3-ethylcarbodiimide

hydrochloride. The mixture was stirred 16 h and then concentrated in vacuo. Following mis addition, the reaction mixture was concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography using 20% diethyl ether in

dichloromethane to yield 3.7 mg of title compound. TLC: Rf = 0.12 (15% diethyl ether/dichloromethane): HPLC (Table A) Rt=17.6 min.

Example 19 A . (4 R,5 S )- b i s - [ ( 1 S ) - N-ca r bo b en zyl oxyisol eu cyI oxy -2 -phen ethyl ]-2,2-di m et hyl - 1,3-d ioxolane. To the resulting compound of example 1A (239 mg. 0.70 mmol) in CH₂CI₂ (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (535 mg, 2.80 mmol), carbobenzyloxy isoleucine (741 mg, 2.80 mmol), and

pyrrolidinopyridine (catalytic). The reaction proceeded for 12 hrs, then was concentrated and purified by silica gel chromatography using 33%

EtOAc/hexane as eluent to afford a mixture of the desired bis-acylated compound as well as monoacylated material (corresponding to the resulting compound of example ISA). These were separated by thick layer silica gel chromatography (1.0 mm) using 5% Et₂O/CH₂CI₂ as eluant. In this manner 79 mg of the title compound was obtained. TLC: Rf (5% Et₂O/CH₂CI₂) = 0.5.

B . The resulting bis-acylated compound of example 19A (62 mg) was hydrolyzed with 90% aqueous trifluoroacetic acid (1.1ml) at 0 °C for 2.5 hrs, then concentrated to dryness in vacuo . The residue was purified by thick layer silica gel chromatography (1.0 mm) using 13% Et₂O/CH₂ Cl₂ as eluent, affording 2.1 mg of the title compound as a white solid. TLC: Rf (14%

Et₂O/CH₂CI₂) = 0.4; NMR (CDCI₃): 7.10-7.50 (m, 20H). 5.00-5.27 (m, 8H), 4.19 (dd, 2H). 3.62 (br s, 2H), 2.80-3.35 (m, 6H), 1.75 (m. 2H), 0.60-1.19 (m, 18H).

Example 20 A . Compound 20. A 13 mg (0.018 mmol) sample of the resultant compound of example 17F was deprotected as indicated in example 6B. A white foam was obtained which was purified by thick layer silica gel chromatography using 4% isopropanol/ methylene chloride as eluant Isolation of the major product band yielded 2.8 mg of white solid. TLC: (4% isopropanol/ methylene chloride) Rf = 0.45; (15% THF/toluene) Rf = 0.49. Example 21

A. 4(R),5(R)-bis-(1'(S)-((S)-aminocyclopentylacetoxy)-2'-phenylethyI))- 2,2-dimethyl-1,3-dioxoIane. A solution of 74 mg (0.12 mmol) of 4(R),5(R)-bis- ((1'S)-1'-((S)-Azidocyclopentylacetoxy)-2'-phenylethyl)-5-(1"(S)-hydroxy-2"- phenylethyl)-2,2-dimemyl-1,3-dioxolane, synthesized as reported in example 17D, in 10 mL of THF was treated with 25 mg of 10% palladium on carbon. The mixture was stirred for 17 h under a slight positive pressure of hydrogen, then filtered and concentrated to 60 mg colorless oil. TLC: (system B) Rf = 0.62.

B. 4(R),5(R)-bis-(1'(S)-((S)-N-(2-benzofuranoyI)- aminocyclopentylacetoxy)-2'-phenylethyl))-2,2-dimethyl-1,3-dioxolane. A solution of 18 mg (0.083 mmol) of the resultant compound of example 21A in 1.5 mL of dichloromethane was treated sequentially, at ambient temperature, with 15 mg (0.091 mmol) of benzofuran-2-carboxylic acid, 18 mg (0.091 mmol) of 1-(3-dimemylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 12 mg (0.091 mmol) of 1-hydroxybenzotriazole hydrate. The mixture was concentrated in vacuo to a volume of several hundred microliters. This residue was purified by thick layer silica gel

chromatography using 3.5% diethyl ether/methylene chloride as eluant Isolation of the major product band yielded 21 mg of colorless oil. TLC: (System C) Rf = .36.

C . Compound 21. A 19 mg (0.022 mmol) sample of the resultant compound of example 17F was taken up in 50 μL of methylene chloride, cooled to 0°, and treated dropwise during 1 min with 450 μL of 90% aqueous trifluoroacetic acid. After stirring for

50 min, the mixture was diluted with methylene chloride and poured into excess saturated sodium bicarbonate solution. The biphasic mixture was separated, and the aqeous phase was extracted with more methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated to white foam, which was purified by thick layer silica gel chromatography using 90: 10:1 methylene chloride/diethyl ether/isopropanol as eluant

The major band was isolated and further purified by preparative HPLC using table G to yield 5 mg of white solid. TLC: (4% isopropanol/ methylene chloride) Rf = 0.35. TLC: (15% THF/toluene) Rf = 0.36.

Example 22

A. Compound 22. A solution of 6.7 mg (0.013 mmol) of the resultant compound of example 16A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 0.0058 mL (0.033 mmol) diisoproplyethylamine and 5.6 mg (0.029 mmol) of 2-napthoyl chloride. The mixture was stirred 2 h and then concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography using 25% diethyl ether in dichloromethane to yield 5.9 mg of the title product. TLC: Rf = 0.22 (15% diethyl ether / dichloromethane). HPLC (Table A) Rt=20.0 min.

Example 23

A. Compound 23. A solution of 10.0 mg (0.020 mmol) of the resultant compound of example 16A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 0.009 mL (0.05 mmol) diisoproplyethylamine and 4.3 mL (0.044 mmol) of 2-furoyl chloride. The mixture was stirred 24 h and then concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography using 25% diethyl ether in dichloromethane to yield 6.1 mg of the title compound. TLC: Rf = 0.07 (15% diethyl ether / dichloromethane): HPLC (Table A) Rt=16.6 min.

Example 24

A. (4R,5S)-4-[(1'S)-N-carbobenzyloxyisoIeucyIoxy-2'- phenethyl]-5-[(1"S)-N-carbobenzyloxyisovaIyloxy-2"-phenethyl]-2,2-dimethyl-1,3-dioxolane. To the resulting compound of example 15 A (16.4 mg, 0.03 mmol) in CH₂CI₂ (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11 mg, 0.06 mmol), carbobenzyloxy valine (14 mg, 0.06 mmol), and pyrrolidinopyridine

(catalytic). The reaction proceeded for 12 hrs, then was concentrated and purified by thick layer silica gel chromatography (0.5 mm) using 5%

Et₂O/CH₂Cl₂ as eluant to yield 11.3 mg of product. B. Compound 24. The resulting compound of example 24 A was hydrolyzed with 90% aqueous trifluoroacetic acid (1 ml) at room temperature for 2 hrs, then concentrated to dryness in vacuo . The residue was purified by thick layer silica gel chromatography (0.5 mm) using 14% Et₂O/CH₂Cl₂ as eluant to yield 1.3 mg of a white solid. TLC: Rf (14% Et₂O/CH₂Cl₂) = 0.33; NMR (CDCI₃): 7.09-7.45 (m, 20H), 5.01-5.25 (m, 8H), 4.15 (dd, 2H), 3.57 (br s, 2H), 2.78- 3.21 (m, 6H), 1.95 (m, 2H), 0.6-1.18 (m, 16H).

Example 25

A . Compound 25. A solution of 6.2 mg (0.012 mmol) of the resultant compound of example 16B in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 4.7 mg (0.028 mmol) of 4-hydroxy-3-methoxybenzoic acid, 0.005 mL (0.031 mmol)

diisoproplyethylamine, 3.3 mg (0.024 mmol) of 1-hydroxybenzotriazole hydrate, and 4.9 mg (0.025 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori de. The mixture was stirred 24 hand then concentrated in vacuo. Following this addition, the reaction mixture was concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography using (1/45/54 v/v/v isopropanol / diethyl ether/ dichloromethane) to yield 2.6 mg of the title compound. TLC: Rf = 0.21 (30% diethyl ether /

dichloromethane). HPLC (Table A) Rt=15.7 min.

Example 26

A. Diethoxy acetic acid. A solution of 1.42 g (7.82 mmol) of Ethyl diethoxy acetate in methanol was saponified with 9.4 mL (9.4 mmol) of 1N NaOH. After 2.5 h the mixture was concentrated in vacuo to 1/3 volume. The residue was dissolved in water and washed with diethyl ether and separated. The aqueous layers pH was adjusted with solid KHSO₄ till acidic (pH =3) and then extracted with ethyl acetate. The organic extracts were washed with saturate NaCl, dried over MgSO₄, filtered, and concentrate in vacuo to yield 0.53 g of product. NMR: (500 MHz., CDCl3) d 4.98 (s, 1H), 3.7 (m, 4 H), and 1.29 (t, 6H). B. Compound 26. A solution of 9.2 mg (0.018 mmol) of the resultant compound of example 16A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 0.008 mL (0.042 mmol) diisoproplyethylamine and 6.2 mg (0.042 mmol) of compound 25A, 0.008 mL (0.046 mmol) diisoproplyethylamine. 5.2 mg (0.038 mmol) of 1-hydroxybenzotriazole hydrate, and 7.4 mg (0.038 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred 16 h. Following this addition, the reaction mixture was concentrated in vacuo and the residue was purified by preparative thick layer silica gel chromatography using (3/160/167 v/v/v isopropanol/ diethyl ether / dichloromethane to yield 7.3 mg of title compound . TLC: Rf = 0.10 (15% diethyl ether / dichloromethane): HPLC (Table A) Rt=18.2 min.

Example 27

A. (4R,5S)-4-[(1'S)-N-carbobenzyloxyisoleucyloxy-2'-phenethyl]-5-[(1"S)-N-/-butyIoxycarbonyIisoIeucyloxy-2"-phenethyl]-2,2-dimethyl-1,3-dioxo)ane. To the resulting compound of example 15 A (80.6 mg, 0.14 mmol) in CH₂CI₂ (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (336 mg, 1.75 mmol), N-r-butyloxycarbonylisoleucine (396 mg, 1.65 mmol),

pyrrolidinopyridine (~5 mg), and heat activated 4A moleculer sieves. The reaction proceeded for 12 hrs, then was filtered, diluted with CH₂CI₂. and washed with saturated NaHCO₃; the organic layer was dried over MgSO₄, filtered, and concentrated to give a residue that was purified by thick layer silica gel chromatography (2.0 mm) using 5% Et₂O/CH₂CI₂ as eluant to yield 114 mg of the desired compound.

B Compound 27. The resulting compound of example 27A (48.1 mg) was hydrolyzed with 83% aqueous trifluoroacetic acid (0.6 ml) at room temperature for 90 min, then concentrated to dryness in vacuo . The residue was purified by thick layer silica gel chromatography (1.0 mm) with 5% MeOH/CH₂Cl₂ as eluent, and 7.6 mg of product was obtained as the trifluoroacetic acid salt. TLC: R_f(5% MeOH/CH₂Cl₂) = 0.33.

Example 28 A. Compound 28. To the resulting compound of example 27B (4.3 mg, 5.53 μmol) in CH₂CI₂ (2 ml) was mixed with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (4.6 mg, 24.4 μmol), 1-hydroxybenzotriazole hydrate (4 mg, 24.4 μmol), 2-pyrimidylthioacetic acid (4 mg, 22.2 μmol), and diisopropylethylamine (2 μl, 11.1 μmol). The reaction proceeded for 12 hrs, then was diluted with CH₂CI₂ and washed with saturated NaHCO3; the organic layer was dried over MgSO4, filtered, and concentrated to afford 1.7 mg of compound 29. TLC Rf (5% MeOH/CH₂Cl₂) = 0.33.

Example 29 A. (4R,5R)-4-((1'S)-1'-((S)-N-Carbobenzyloxvalyloxy)-2'-phenylethyl)- 5-(1 "(S)-((S)-N-Carbobenzyloxaminocyclopentylacetoxy)-2"- phenylethyI)-2,2-dimethyl-1,3-dioxoIane. A solution of 20 mg (0.035 mmol) of t he resultant compound of example 17F in 1 mL of methylene chloride was cooled to 0° and treated with 18 μL (105 μmol) of dϋsopropylethlamine folowed by 13 μL (89 μmol) of benzyl chloroformate. The mixture was stirred for 16 h, warming slowly to ambient temperature. The mixture was concentrated in vacuo, and the colorless residue purifed by thick layer silica gel chromatography using 4% diethyl ether/methylene chloride as eluant Isolation of the major band yielded 28 mg of colorless oil.

C . Compound 29. A 26 mg (0.031 mmol) sample of the resultant compound of example 29A was deprotected as indicated in example 21 C. A white foam was obtained which was purified by silica gel chromatography using a gradient of 4:1 to 1:1 methylene chloride to system E as eluant to yield 14 mg of colorless oil; TLC (system E): Rf = 0.54. HPLC (Table A): Rt = 20.4 min.

Example 30 A . Compound 30. The resulting compound of example 27B (31 mg, 0.04 mmol) in CH₂CI₂ (2 ml) was mixed with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol), 1-hydroxybenzotriazole hydrate (48 mg, 0.36 mmol), 4-hydroxy-3-methoxycinnamic acid (69 mg, 0.36 mmol). and diisopropylethylamine (21 μl, 0.12 mmol). The reaction proceeded for 12 hrs, then was concentrated and purified by thick layer silica gel chromatography (2 × 1.0 mm plates) using 25% Et₂O/ CH₂CI₂ as eluant to yield 1.1 mg of the desired compound. TLC: Rf (25% Et₂O/ CH₂CI₂) - 0.25.

Example 31

A . Compound 31. The resulting compound of example 27B (15.8 mg, 0.02 mmol) in CH₂CI₂ (2 ml) was mixed with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13 mg, 0.07 mmol), 1-hydroxybenzotriazole hydrate (9 mg, 0.07 mmol), phenylpyruvic acid (10 mg, 0.06 mmol), and diisopropylethylamine (15 μl, 0.08 mmol). The reaction proceeded for 12 hrs, then was concentrated and purified by thick layer silica gel chromatography (1.0 mm) using 25% Et₂O/CH₂CI₂ as eluent. The desired compound was isolated and repurified with 5% Et₂O/CH₂CI₂ to afford 1.9 mg of the title compound. TLC: Rf (5% Et₂O/ CH₂CI₂) = 0.13.

Example 32

A. (4R,5R)-4-((1'S)-1'-((S)-N-(3-Cyanobenzoylvalyloxy))-2'-phenylethyl)-5-(1''(S)-((S)-N-Carbobenzyloxisoleucyl)-2"-phenylethyI).

2,2-dimethyl-1,3-dioxolane. A solution of 105.4 mg (0.179 mmol) of the resultant compound of example 15A in dichloromethane was treated

sequentially, at ambient temperature under an atmosphere of nitrogen, with 77.7 mg (0.357 mmol) N-t-butyloxycarbonyl-valine, 69.0 mg ( 0.357 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 12 mg (0.091 mmol) of 1-hydroxybenzotriazole hydrate, and catalytic 4-dimethylaminopyridine. The mixture was stirred 60 h and then concentrated in vacuo. The residue was purified by low pressure silica gel column

chromatography using a 0 - 1.5% diethyl ether in dichloromethane as eluent to yield 109.6 mg of product. TLC: Rf = 0.78 (5% diethyl ether/dichloromethane).

B . Compound 32. A solution of 12.2 mg (0.015 mmol) of the resultant compound of example 32A was dissolved in 3 drops of 90% aqueous

trfluoroacetic acid. After 45 min. another 3 drops of 90% aqueous

trfluoroacetic acid was added. After 1 h (total) this mixture was concentrated in vacuo. A solution of the crude isolate was treated with 0.007 mL (0.039 mmol) diisopropylethylamine and 3.0 mg (0.018 mmol) 3-cyanobenzoyl chloride. The mixture was stirred 16 h and then concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a 15% diethyl ether in dichloromethane as eluent to yield 5.1 mg of title compound. TLC: Rf = 0.27 (15% diethyl ether / dichloromethane): HPLC (Table A) Rt = 17.6 min.

Example 33

A. Compound 33. A solution of 7.5 mg (0.010 mmol) of the resultant compound of example 32A was dissolved in 3 drops of 90% aqueous

trfluoroacetic acid. After 45 min. another 3 drops of 90% aqueous

trfluoroacetic acid was added. After 1 h (total) this mixture was concentrated in vacuo. A solution of the crude isolate was treated with 0.004 mL (0.024 mmol) diisopropylethylamine and 0.002 mL (0.014 mmol) 4- morpholinecarbonyl chloride. The mixture was stirred 1 h and then

concentrated in vacuo. The residue was purified by preparative thick layer silica gel chromatography using 25% diethyl ether in dichloromethane to yield 2.7 mg of the title product. TLC: Rf = 0.06 (15% diethyl ether/

dichloromethane): HPLC (Table A) Rt=17.8 min.

Example 34

A. (4R,5S)-4-[(1'S)-N-carbobenzyloxyisoIeucyIoxy-2'- phenethyl]-5-[(1"S)-2-pyridylacetoxy-2"-phenethyI]-2,2-dimethyl-1,3-dioxolane. To the resulting compound of example 15A (7 mg. 0.01 mmol) in CH₂CI₂ (1 ml) was placed 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7 mg, 0.04 mmol), 2-pyridylacetic acid hydrochloride salt (6 mg, 0.04 mmol), diisopropylethylamine (8 ul, 0.05 mmol), and dimethylaminopyridine (catalytic). The reaction proceeded for 12 hrs at room temperature, then was concentrated and purified directly by thick layer silica gel chromatography (1.0 mm) with 10% Et₂O/CH₂CI₂ to yield 5 mg of the title compound.

B. Compound 34. The resulting compound of example 34 A was reacted in 90% aqueous trifluoroacetic acid (0.55 ml) at room temperature for 75 min. then concentrated to dryness in vacuo . The residue was purified by silica gel chromatography using 5% MeOH/CH₂CI₂ as eluant, affording 1.4 mg of product. TLC: Rf (5% MeOH/CH₂Cl₂) = 0.50.

Example 35

A. (4R,5S)-4-[(1'S)-N-carbobenzyloxyisoIeucyloxy-2'- phenethyl]-5-[(1"S)-O-carboisopropyloxy-2"-phenethyI]-2,2-dimethyl-1,3-dioxolane. To the resulting compound of example 15A (12 mg, 0.02 mmol) in pyridine (1 ml) was placed a large excess of

isopropylchloroformate (600 μl) and dimethylaminopyridine (catalytic), and the reaction stirred at room temperature overnight. The reaction mixture was then filtered, concentrated, diluted with CH₂CI₂. filtered again, concentrated, and the residue was purified by thick layer silica gel chromatography (0.5 mm) using 2% Et₂O/CH₂CI₂ as eluent to yield 4 mg of the title compound . TLC: Rf(2%Et₂O/CH₂CI₂) = 0.74.

B. Compund 35. The resulting compound of example 35 A was dissolved in MeOH (1 ml) containing concentrated HCL (~100 μl), and the reaction stirred for 90 min. After concentration to dryness invacuo, the residue was purified by silica gel chromatography using 5% Et₂O/CH₂CI₂ as eluant, affording 0.3 mg of product. TLC: Rf (5% Et₂O/CH₂CI₂) = 0.15.

Example 36 A. (4R,5S)-4-[(1'S)-N-carbobenzyloxyisoleucyloxy-2'-phenethyl)-5-((1"S)-acetoxy-2^,'-phenethyl)]-2,2-diιnethyl-1,3-dioxolane. To the resulting compound of example 15A (7 mg, 0.01 mmol) in CH₂CI₂ (1 ml) was placed pyridine (15 ul, 0.19 mmol) and acetyl chloride (12 ul, 0.17 mmol), and the reaction proceeded at ambient temperature for 12 hrs. The reaction mixture was then diluted with CH₂CI₂ and washed with saturated NaHCO₃. and the organic layer was dried over MgSO₄. Filtration and

concentration gave a residue which was passed over a silica gel plug, eluting with 2% Et₂O/CH₂CI₂ to remove polar impurities. Concentration of the eluent provided a pale yellow oil (5 mg). TLC: Rf (2% Et₂O/CH₂CI₂) = 0.43. B . The resulting compound of example 36 A was dissolved in deoxygenated 90% aqueous triflouroacetic acid (1 ml) at 0 °C where the reaction proceeded for 30 min, then was concentrated in vacuo to dryness. The residue was chromatographed on a silica gel column using 5% Et₂O/CH₂CI₂ as eluent, yielding compound 35 (1.2 mg) as a colorless substance. TLC: Rf (5 %

Et₂O/CH₂CI₂) = 0.16.

Example 37

A. f-Butyldimethylsiloxyphenylacetic acid. The title compound was prepared in two steps as follows: 1) To a solution of 2-hydroxyphenylacetic acid (137 mg, 0.9 mmol) in DMF (5 ml) was added imidazole (184 mg, 2.7 mmol) and r-butyldimethylsilyl chloride (407 mg, 2.7 mmol), and the reaction stirred at ambient temperature overnight. Dilution with EtOAc, followed by washing of the organic layer with saturated NH4CI and water (2x), provided, after drying over MgSO4. filtration and concentration, the bis-silylated hydroxy acid as a pale yellow oil which was used in the subsequent reaction without purification. 2) The resulting compound was dissolved and stirred in 3/1/1/ glacial acetic acid/water/THF (7 ml) for 90 min at room temperature, then was concentrated to dryness in vacuo to afford the siloxy acid (131 mg) as an oil.

B . (4R,5S )-4- [ (1 ' S ) -N-carb obenzyIoxyisoI eucyloxy-2 ' -phenethyl ] -5-[ ( 1 " S)-(2 -tertb u tyl d im ethy ls i loxyp henylaceto xy ) -2"-phenethyl]-2,2-d i methyl- 1 ,3-d ioxoIane. To as solution of the resulting compound of example 15A (8.9 mg, 0.02 mmol) in CH₂CI₂ (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol). the resulting compound of example 37A (25 mg, 0.09 mmol), and dimethylaminopyridine (catalytic). The reaction proceeded for 12 hrs, then was concentrated and purified by thick layer silica gel chromatography (0.5 mm) with 2% Et₂O/ CH₂CI₂ as eluent. The desired compound (5.3 mg) was isolated as a white solid. TLC: Rf (2% Et₂O/CH₂CI₂) = 0.47.

C. Compound 37. The resulting compound of example 37B was

hydrolyzed with 90% aqueous trifluoroacetic acid (1.1 ml) at room temperature for 90 min, then concentrated to dryness in vacuo . The residue was purified by thick layer silica gel chromatography (0.5 mm) using 14% Et₂O/CH₂Cl₂ as eluant to yield 0.3 mg of white solid. TLC: Rf (13% Et₂O/CH₂CI₂ ) - 0.19.

Claims

1. A compound capable of inhibiting HIV aspartyl

protease, represented by the formula:

and pharmaceutically acceptable salts thereof,

wherein B is H, (C1-C5)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl,

(C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl or phenyl, or

(C1-C2)-alkyl substituted with CONH₂, OH, OCH₃ or SCH₃;

wherein J is NHC(O)M, wherein M is Ar (C1-C4)- alkyl which may be substituted with Ar, (C2-C4)- alkenyl which may be substituted with Ar or azide; wherein Ar is a benzofused heterocycle with 1-2 heteroatoms independently chosen from O, N or S; morpholino, phenyl, 2-naphthyl, 9-fluorenyl,

1-benzotriazole or phenyl substituted with 1-3 substituents independently selected from the group consisting of cyano, hydroxyl, amino, dimethylamino, methoxy, benzyloxy and halo;

wherein Z is hydrogen, (C1-C4)-straight or branched alkyl, (C2-C4) -straight or branched

alkenyl, phenyl, Ar-substituted (C1-C4)-straight or branched alkyl, Ar-substituted (C2-C4)-straight or branched alkenyl, O-(C1-C5)-straight or branched alkyl or alkenyl, O-(C5-C6)-cycloalkyl or

cycloalkenyl, or CH-B-J where B and J are defined above.

2. A compound of Claim 1 having a molecular weight from about 450 to about 1100 atomic mass units.

3. A compound of Claim 1 represented by any of the

structures in Table 1 and Table 2.

4. A compound of Claim 1 represented by the formula:

5. A compound capable of inhibiting HIV aspartyl

protease, represented by the formula:

wherein B is selected from the group consisting of 2-pyridylmethyl, isopropoxy, methyl and

(20hydroxyphenyl)methyl.

6. A compound capable of inhibiting HIV aspartyl

protease, represented by the formula:

and pharmaceutically acceptable salts thereof,

wherein A is hydrogen, (C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl, azide, phenyl, hydroxyl, NH-L, O-L,

CH₂-NH-L, CH₂-O-L, Ar-substituted (C1-C4)- straight or branched alkyl, Ar-substituted (C2-C4)-straight or branched alkenyl;

wherein L is Ar-carbonyl, Ar-oxycarbonyl or (C1-C2)-alkoxycarbonyl which may be substituted with an Ar group;

wherein Ar is a benzofused heterocycle with 1-2 heteroatoms independently chosen from O, N or S; morpholino, phenyl, 2-naphthyl, 9-fluorenyl,

l-benzotriazole or phenyl substituted with 1-3 εubstituents independently selected from the group consisting of cyano, hydroxyl, amino, dimethylamino, methoxy, benzyloxy and halo;

wherein B is H, (C1-C5)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl. (C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl or phenyl, or

(C1-C2)-alkyl substituted with CONH₂, OH, OCH₃ or SCH₃;

wherein D is hydrogen or oxygen;

wherein E and E' are independently (C1-C2)-alkyl or C2-alkenyl;

wherein G and G' are independently (C1-C4)- straight or branched alkyl, (C2-C4)-straight or branched alkenyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, phenyl or phenyl substituted with a substituent selected from the group consisting of hydroxy, (C1-C4)-straight or branched alkoxy, benzyloxy, halo, amino, dimethylamino, aminomethyl and dimethylaminomethyl; and

wherein K is (C1-C8)-straight or branched alkane which may be substituted with one or two Ar groups, (C2-C8)-straight or branched alkene which may be substituted with one or two Ar groups or

wherein A, B and D are independently

selected from the groups recited above, wherein the stereochemistry at carbon position 1, 2 or 3 are independently R or S.

7. A compound of Claim 6 having a molecular weight of from about 450 to about 1100 atomic mass units.

8. A composition for the therapeutic treatment of HIV-1 infection, including AIDS, ARC, AIDS-related

dementia and non-symptomatic HIV-1 infection. comprising a compound of Claim 1, in a physiologically acceptable vehicle.

9. A composition of Claim 8, wherein the compound is represented by any one of the compounds shown in Tables 1 and 2.

10. A composition of Claim 9, further comprising

administering the composition with an anti-HIV agent capable of inhibiting cell entry, reverse transcription, integration of viral DNA into the patient's cellular DNA, viral uncoating, integration of the virus' DNA into the hosts' genome, trans-activators of the viral nRNA transcription such as tat or rev, and/or other inhibitors of the HIV aspartyl protease.

11. A composition for the therapeutic treatment of

infections by viruses which rely on an aspartyl protease for an obligatory event in their life cycle, including HIV-2 and HTLV-1, comprising a compound of Claim 1 in a physiologically acceptable vehicle.

12. A composition of Claim 11, wherein the compound is represented by any one of the compounds shown in Tables 1 and 2.